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Integrated Grants is a virtual database currently indexing funded research resources including NIH Research Portfolio Online Reporting Tool (RePORT) (current grants, updated monthly), International Alzheimer’s Disease Research Portfolio (IADRP) database and ResearchCrossroads (1970-2008, defunct as of 2009).
Note: ResearchCrossroads is no longer in service.
(last updated: Mar 11, 2022)
Funding Grants| Project Number | PI Names | Project Title | Funding Year | Abstract | Funding Institute | Grant Code | ||
|---|---|---|---|---|---|---|---|---|
| 1R01NS123642-01 | Muotri, Alysson R. | The impact of hiPSC-derived microglia in human brain development in health and disease | 2021, funded from 08/01/2021 to 07/31/2022 | Abstract The main goal of this project is to determine the contribution of human microglia in the establishment of early neural networks during development in healthy and autistic conditions. Although the exact cause of Autism Spectrum Disorders (ASD) remains unclear, epigenetic, genetic and environmental factors are at play. Given that ASD is a complex multifactorial disorder and that epigenetic modifications have been shown to control microglial phenotypes/plasticity, we hypothesized that microglial epigenetic signature might influence neuronal development. Given that microglia originate in the periphery and later invade the brain, they are most likely the first brain cell type to be exposed to an environmental factor or at least be impacted by the environmental factor given their role as gate keepers of the brain. Therefore, a better understanding of the genetic, environmental or a synergistic impact of both, will pave the way to a better understanding of human neurodevelopment and human microglial roles during this process yielding to the discovery of novel therapeutic targets and efficient therapies for a broad range of neurological disorders including ASD. Thus, with this project, we aim to establish whether and how human microglia interfere with neural network establishment and if high-risk ASD epigenetic genes could alter their function and their role during human neurodevelopment. Based on our preliminary data we propose the following specific aims are: Aim 1: Determine the role of healthy human microglia on healthy brain cortical organoids (BCO), Aim 2: Measure the impact of microglia carrying ASD mutations on BCO development and function, and Aim 3: Impact of environmental ASD-risk factors in combination with underlying genetic predisposition: the two-hit hypothesis. Here we will test the isolated and additive effect of ASD-related environmental factors on the function of microglia and its impact on BCO physiology. | National Institute Of Neurological Disorders And Stroke | R01 | Affect, Appearance, ASD patient, autism spectrum disorder, autistic, base, Biological Models, Brain, brain cell, cell type, Cells, Complex, Data, Development, Disease, Environmental Impact, Environmental Risk Factor, Epigenetic Process, Experimental Models, experimental study, Exposure to, fetal, first responder, Gene Expression, Genes, Genetic, Genetic Predisposition to Disease, Genetic Transcription, genetic variant, Goals, Health, high risk, Human, Impairment, induced pluripotent stem cell, Invaded, Measures, Microglia, Modeling, Modification, Molecular, mutant, Mutation, Nerve Degeneration, nervous system disorder, neural network, Neuraxis, neurodevelopment, Neurodevelopmental Disorder, neuron development, Neurons, new therapeutic target, Organoids, Patients, Phagocytosis, Phenotype, Physiological, Physiology, Play, Population, Process, Risk Factors, risk variant, Role, single-cell RNA sequencing, Synapses, synaptic pruning, synaptogenesis, Testing, Time, XCL1 gene | Department of Pediatrics, UNIVERSITY OF CALIFORNIA, SAN DIEGO, La Jolla, CA 92093, United States |
| 1R01HL159213-01 | Manatunga, Amita K. | Developing statistical image analysis tools for non-invasive monitoring of anemia in low birth weight infants | 2021, funded from 08/01/2021 to 05/31/2022 | Project Summary Our proposal is motivated by the need to develop non-invasive tools for monitoring anemia in very low birth weight (VLBW; birth weight < 1,500 grams) and reduce the number of routine painful, invasive blood sampling procedures (phlebotomy) that may alter infant neurodevelopment and behavior. Recently, a new smartphone application [Mannino et al., Nature Communications, 9, 4924 (2018)] that collects and analyzes clinical pallor in patient-sourced fingernail photos and image metadata has been developed to predict hemoglobin levels. The app uses a robust multi-linear regression model that incorporates summary color intensity values (average across pixels) of fingernail photos well as the image metadata generated by the device capturing the image to predict patient's hemoglobin level. While the current app algorithm is simple and easy to implement, there are notable limitations. First, it does not fully leverage the rich spatial information available in fingernail photos by calculating a simple average value. Second, the current algorithm is trained using only adults, whose clinical characteristics are vastly different from infants. The 95% limit of agreement between the app-predicted and blood sample-based hemoglobin level for adults is reported as 2.4 g/dL, which is higher than the Clinical Laboratory Improvement Amendments specification variance of 1.0 g/dL, and will likely increase in VLBW infants given their tiny, non-specific fingernail beds. Such strict error requirements and heterogeneity in populations demand more accurate and tailored algorithms than what the current app employs. Lastly, a framework for applying the app to minimize blood draws across the longitudinal care continuum for VLBW infants is currently lacking. With these considerations, we propose (Aim 1) to develop a new image analysis algorithm (IAA) that produces non-invasive, accurate and stable prediction of hemoglobin level. The IAA will be based on a novel principal component analysis method that provides a non-parametric and parsimonious means to jointly model high- dimensional photos and image metadata, while fully leveraging their spatial structures and co-varying patterns. We will also consider a new partial least squares approach as an alternative method. We will train and validate the IAA based on adult data as well as VLBW infant data. In Aim 2, we will develop a new clustering method to study sub-population structures of fingernail photos and image metadata and study their relationships with the underlying physiological mechanisms of anemia. This approach will allow us to formulate a non-invasive image- based screening tool by identifying clusters of VLBW infants with high anemia risk. In Aim 3, we will develop data-driven tools that leverage longitudinal, patient-level clinical data and IAA predictions to achieve the overarching clinical goal of minimizing the number of blood draws in VLBW infants throughout the care continuum. Our proposal will use the data of VLBW infants monitored at three level III neonatal intensive care units in Atlanta. The proposed methods are generally applicable to a wide variety of settings with diverse and complex modalities of clinical data. | National Heart, Lung, And Blood Institute | R01 | Address, Adult, Agreement, Algorithmic Analysis, Algorithms, Anemia, base, Beds, Behavior, Birth Weight, Blood, Blood specimen, Characteristics, Clinical, Clinical Data, clinical decision-making, Clinical Laboratory Improvement Amendments, Color, Communication, Complement, Complete Blood Count, Complex, Continuity of Patient Care, Data, Data Analyses, design, Devices, Diagnosis, Dimensions, Ensure, Goals, Gold, Hemoglobin, Hemoglobin concentration result, Hemorrhage, Heterogeneity, high dimensionality, Hybrids, Image, Image Analysis, improved, Infant, infant monitoring, Inflammatory, inflammatory disease of the intestine, intestinal injury, Knowledge, Laboratories, Lead, learning strategy, Least-Squares Analysis, Linear Regressions, Longitudinal Studies, Low Birth Weight Infant, Measurement, Metadata, Methods, Modality, Modeling, Monitor, Nature, Necrotizing Enterocolitis, Neonatal Intensive Care Units, neurodevelopment, non-invasive imaging, non-invasive monitor, noninvasive diagnosis, novel, Pain, Pallor, Patients, Pattern, Performance, Physicians, Physiological, Population, postnatal, postnatal period, prediction algorithm, premature, Premature Birth, Principal Component Analysis, Procedures, Recording of previous events, recruit, Reporting, Research Project Grants, response, Risk, Screening procedure, smartphone Application, Source, statistical learning, Structure, Structure of nail of finger, Subgroup, Testing, Time, tool, Training, unsupervised learning, user friendly software, user-friendly, Venous blood sampling, Very Low Birth Weight Infant | Department of Biostatistics & Other Math Sci, EMORY UNIVERSITY, Atlanta, GA 30322, United States |
| 1R01HL159546-01 | Stucke, Astrid G | Mechanisms of opioid and sedative-induced respiratory depression | 2021, funded from 08/18/2021 to 06/30/2022 | Project Summary The recent increase in overdose deaths, fueled by an increase in opioid addiction and the availability of highly potent opioids like fentanyl has turned opioid-induced respiratory depression (OIRD) into a public health problem. In addition, OIRD has long been recognized as a major risk factor in the perioperative period where it can require intensified postoperative management or, on rare occasions, result in hypoxic injury. Total opioid dose and the concomitant use of sedative drugs like benzodiazepines are significantly associated with an increased risk of OIRD. Consequently, there is great urgency to develop drugs that can alleviate OIRD without reversing analgesia or causing withdrawal. Over the past 20 years, development of respiratory stimulating drugs has been guided by the central dogma that the preBötzinger Complex (preBötC) is the brainstem site that controls respiratory rate and pattern generation, that OIRD is due to an effect on the preBötC, and that to counteract OIRD drugs must stimulate the preBötC. However, drugs that were developed in animals to stimulate breathing through effects on the preBötC were not sufficiently effective in humans. Based on our published and preliminary data we propose a novel paradigm where the respiratory pattern is generated in the preBötC but two separate brainstem areas, the Parabrachial Nucleus/ Kölliker-Fuse Complex (PBN/KF), and the caudal medullary raphe (CMR) contribute excitatory drive to preBötC neurons responsible for switching in particular from expiration to inspiration and thus determine respiratory rate. These areas are also highly sensitive to clinical opioid doses. Injection of the opioid antagonist naloxone into these areas completely prevented OIRD, even at high opioid doses. The goal of our study is to determine whether stimulation of neurons in the PBN/KF and CMR can overcome OIRD and whether there are limits to this effect. We will use our adult, in vivo decerebrate rabbit preparation, which allows to investigate opioid- and other drug effects on single neurons and in functionally identified cell nuclei without baseline anesthesia and with neuronal networks and physiological reflexes intact. We will measure how much opioids and other sedatives depress neuronal function in and synaptic inputs to the PBN/KF, CMR, and preBötC. We will then test how much AMPA and NMDA receptor modulators, i.e., drugs that enhance the function of excitatory AMPA and NMDA receptors, increase the activity of PBN/KF, CMR, and preBötC neurons, whether this can offset the depression from opioids and sedatives and whether the effect is limited at high opioid and sedative doses. The results will significantly improve our insights into the neuronal mechanisms of drug-induced respiratory depression and into potential therapeutic approaches and limitations. | National Heart, Lung, And Blood Institute | R01 | Absence of pain sensation, Acute, Adult, Affect, AMPA Receptors, Analgesics, Anesthesia procedures, Animals, Apnea, Area, base, Benzodiazepines, Brain Stem, Breathing, Carbon Dioxide, Cell Nucleus, Clinical, Complex, Data, Development, Dose, drug development, effectiveness evaluation, expiration, Fentanyl, Frequencies, Generations, Glutamate Receptor, Glutamates, Goals, Human, Hypoxia, improved, In Vitro, in vivo, Infusion procedures, Injury, insight, Intravenous, Ketamine, Location, Measures, Mediating, Mental Depression, Microinjections, Minor, Modeling, N-Methyl-D-Aspartate Receptors, N-Methylaspartate, Naloxone, Neurons, novel, Opiate Addiction, Opioid, Opioid Antagonist, opioid injection, Oryctolagus cuniculus, overdose death, parabrachial nucleus, Pattern, Perioperative, Pharmaceutical Preparations, Phase, Physiological, Play, Postoperative Period, preBotzinger complex, Preparation, prevent, Public Health, Publishing, Reflex action, respiratory, response, Risk, Risk Factors, Role, sedative, Site, Synapses, Testing, Therapeutic, Tidal Volume, Ventilatory Depression, Withdrawal | Department of Anesthesiology, MEDICAL COLLEGE OF WISCONSIN, Milwaukee, WI 53226, United States |
| 1R01EY033022-01 | Meyer, Jason Stephen | Establishing a human cellular model of retinal ganglion cell compartmentalization in neurodegeneration and neuroinflammation | 2021, funded from 09/01/2021 to 08/31/2022 | SUMMARY Retinal ganglion cells (RGCs) are the projection neurons of the retina that serve as the connection between the eye and the brain. In this role, they allow for the transmission of visual information to thalamic targets, with damage to this pathway in injury or disease leading to vision loss or blindness. Glial cells, particularly astrocytes and microglia, are found adjacent to RGCs within the optic nerve, where they maintain homeostatic conditions for RGCs to ensure proper health and functionality. Conversely, neuroinflammatory conditions occur when astrocytes and microglia are induced to adopt a reactive state, leading to the degeneration of RGCs. Neuroinflammation has been associated with a variety of neurodegenerative diseases, but the pathology of neuroinflammation in glaucoma is unique due to the highly localized nature of glial reactivity in the optic nerve head as RGC axons exit the eye, correlated with the initial site of injury along RGC axons in glaucoma. While animal models have demonstrated the importance of glia in neuronal development and degeneration, important differences exist between animal models and human patients, including low conservation of RGCs as well as numerous functional differences in glia. As such, the development of a human model of these cellular interactions would further expand our understanding of how glia provide support for RGCs, as well as how glia respond during neuroinflammatory conditions leading to the degeneration of RGCs in glaucoma. Human pluripotent stem cells (hPSCs) can serve as powerful in vitro models for the study of retinal development and disease, with previous studies demonstrating the ability to model RGC neurodegeneration in vitro. However, these studies have not focused upon the compartmentalized nature of RGCs, nor how reactive glia disproportionally affect the axons of RGCs in neuroinflammatory conditions. Thus, to address the shortcomings of existing hPSC-based models of glaucoma and to better recapitulate interactions between RGCs and glia, the current application leverages a robust and reproducible in vitro model to recreate the spatial interactions of glia upon human RGC axons relevant to the neurodegenerative phenotypes observed in glaucoma. Interactions between glia and RGC compartments will be analyzed in quiescent and reactive states, and the functional consequences of reactive glia upon RGC axons will be assessed phenotypically, transcriptionally, and functionally to identify the extent to which reactive glia modulate RGC neurodegeneration. The successful pursuit of the following aims will leverage a powerful microfluidic platform for the analysis of RGC axons to include the neuroinflammatory effects of glia and will provide opportunities to further elucidate fundamental neurodegenerative mechanisms in human RGCs, as well as to develop novel therapeutic approaches to slow or reverse neurodegeneration. | National Eye Institute | R01 | Address, Adopted, Affect, Animal Model, Astrocytes, Axon, Axonal Transport, Blindness, Brain, Cell Compartmentation, Cell Differentiation process, Cell model, cell type, Cells, Coculture Techniques, Dendrites, Development, Disease, Disease Progression, Ensure, Eye, Gene Expression Profile, Genetic Transcription, Glaucoma, Health, Human, human model, human pluripotent stem cell, In Vitro, in vitro Model, Injury, Label, Lead, Length, Microfluidics, Microglia, Modeling, Morphology, Mutation, Nature, Nerve Degeneration, Neuraxis, Neurodegenerative Disorders, neurodegenerative phenotype, Neuroglia, neuroinflammation, neuron development, Neurons, neurotoxic, neurotoxicity, novel, novel therapeutic intervention, Optic Disk, Optic Nerve, patch clamp, Pathology, Pathway interactions, Patients, Phenotype, Play, real-time images, Reproducibility, Retina, retinal axon, retinal ganglion cell degeneration, Retinal Ganglion Cells, retinal neuron, Role, Signal Pathway, Site, stem cell model, Study models, success, System, Testing, Thalamic structure, transcriptome sequencing, transmission process, visual information | Department of Genetics, INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS, Indianapolis, IN 46202, United States |
| 1R01AG077020-01 | Ferrando, Adolfo A. (Contact), Rabadan, Raul | The role of PHF6 in the control of hematopoietic stem cell aging. | 2021, funded from 09/01/2021 to 05/31/2022 | Project Summary/Abstract As life expectancy increases age-associated pathologies have become a major health problem. It is now recognized that stem cell aging is a driver of systemic and organ-specific functional decline. In the hematopoietic system stem cell aging is characterized by accumulation of immunophenotypically-defined hematopoietic stem cells (HSCs) with impaired self-renewal capacity and altered differentiation programs with increased generation of myeloid populations and decreased lymphoid potential. Here we show that genetic loss of Plant Homeodomain Factor 6 (PHF6) results in increased HSC serial transplantation capacity and abrogates the development of age-associated hematopoietic decay including the accumulation of functionally exhausted HSCs displaying myeloid differentiation bias and impaired lymphoid potential. Our central hypothesis is that loss of Phf6 reconfigures the epigenetic landscape of HSCs blocking the initiation and/or progression of age-associated functional decline. Here we will apply the combined expertise of the Ferrando and Rabadan labs in hematopoiesis and computational biology to explore in depth the hematopoietic phenotypes and mechanisms of PHF6 inactivation in HSC aging. Towards this goal we will analyze the stem cell compartment in Phf6 conditional knockout mice and after CRISPR-directed PHF6 inactivation in human hematopoietic stem cells, leveraging in vitro and in vivo stem cell assays in combination with advanced computational analytical tools applied to single cell transcriptomics and epigenomics. These studies will ultimately facilitate the development of new targeted therapies aimed at improving the engraftment capacity of hematopoietic stem cells from aged donors and for the treatment of pathologies resulting from age-associated HSC deterioration. | National Institute On Aging | R01 | Age, aged, Aging, Anabolism, analytical tool, Animal Model, Biological Assay, Bone Marrow, Cell Adhesion, cell age, Cell Aging, Cell Compartmentation, Cell Cycle, Cell Cycle Kinetics, Cell division, Cell model, cell motility, Cell Nucleolus, Cell physiology, Cell Proliferation, Cells, Chromatin, Clustered Regularly Interspaced Short Palindromic Repeats, Colony-Forming Units Assay, Complex, Computational Biology, conditional knockout, cytokine, Deacetylase, Deterioration, Development, DNA Damage, Engraftment, Epigenetic Process, epigenomics, Event, exhaust, experimental study, fitness, functional decline, Generations, Genes, Genetic, Genetic Transcription, genome integrity, Goals, Health, Hematopoiesis, Hematopoietic, hematopoietic stem cell aging, hematopoietic stem cell self-renewal, Hematopoietic stem cells, Hematopoietic System, homeodomain, Homing, Human, Impairment, improved, In Vitro, in vivo, Inflammation, Inflammatory, Knock-out, Knockout Mice, leukemic transformation, Life Expectancy, Lymphoid, Mediating, Mediator of activation protein, Metabolism, Molecular, Myelogenous, new therapeutic target, Nucleosomes, Organ, Pathology, Phenotype, Plants, Play, Population, Population Decreases, Positioning Attribute, programs, Proteins, Regulation, replication stress, response, Ribosomes, Role, self-renewal, senescence, Somatic Mutation, stem, stem cell aging, stem cell function, stem cells, Testing, therapeutic development, Therapeutic Intervention, transcriptomics, Translations, Transplantation | COLUMBIA UNIVERSITY HEALTH SCIENCES, New York, NY 10032, United States |
| 1R01CA262506-01 | Denardo, David G (Contact), Deselm, Carl | Re-wiring PDAC Tumor Immunity Through Dendritic Cells | 2021, funded from 09/22/2021 to 08/31/2022 | PROJECT SUMMARY The prognosis for pancreatic ductal adenocarcinomas (PDAC) patients is dismal. This is likely due to the presence of a uniquely suppressive tumor microenvironment (TME) that is dominant in most PDAC. Our data suggest immune priming by conventional dendritic cells (cDCs) may be a necessary barrier to overcome to generate lasting immunity in PDAC patients. cDCs are central for generating tumor antigen?specific T cell responses. Our new data show that cDCs are severely dysfunctional in patients with PDAC. This dysfunction is driven by two mechanisms: 1) We recently reported that PDAC patients have impaired cDC development in their bone marrow, and this leads to functional depletion of circulation pre-DCs, and poor response to checkpoint inhibitors. 2) We recently showed that even when cDC development is not fully impaired, cDC1s are physically/biochemically excluded from the PDAC TME. These mechanisms to the loss of stereotactic body radiation therapy (SBRT)-induced priming of tumor antigen-specific T cell responses and ultimately failed tumor control in animal models. We overcame both of these dysfunctional barriers by targeting cDC1s using a combination of systemic treatment with FMS-like tyrosine kinase 3 ligand (FLT3L) and CD40 agonists. Our pre- clinical data are exceptionally strong and have placed us in a unique position to translate these findings into PDAC patients. Our central hypothesis is that targeting cDC can unlock responsiveness to RT by generating lasting anti-tumor immunity. We will expand test this hypothesis in three specific aims. Aim 1. Determine the safety and efficacy of the combination of CDX-301 plus CDX-1140 and SBRT in locally advanced PDAC patients Aim 2. Determine the mechanisms by which FLT3L plus a CD40 agonist induce anti-tumor immunity. Aim 3. Determine if FLT3L plus CD40 agonists improves responsiveness to checkpoint immunotherapy. Impact. PDAC patient responses to conventional radiation therapy have been disappointing. Our data strongly support the use of FLT3L and CD40 agonist to enhance patient responsiveness to RT and generate long-term anti-tumor immunity. Our team is well-positioned to test our central hypothesis directly in clinical and experimental studies. | National Cancer Institute | R01 | Aftercare, Agonist, Animal Model, Animals, antigen-specific T cells, Antigens, Automobile Driving, Biochemical, Biological Assay, Biological Markers, Blood Circulation, Bone Marrow, cancer cell, checkpoint therapy, chemotherapy, Clinical, Clinical Data, Clinical Research, clinical translation, Clinical Trials, cohort, Combined Modality Therapy, Conduct Clinical Trials, Correlative Study, Cross Presentation, Cytometry, Cytotoxic agent, Data, Dendritic Cells, density, Development, experimental study, fetal liver kinase-2, Functional disorder, Future, Human, Image, Immune, immune checkpoint blockade, Immune checkpoint inhibitor, Immunity, Immunologic Tests, Immunologics, Immunosuppression, immunosuppressive macrophages, Immunotherapy, Impairment, improved, Infiltration, Ligands, Limes, Malignant neoplasm of pancreas, Malignant Neoplasms, member, mouse model, Myelogenous, Nature, Operative Surgical Procedures, Pancreatic Ductal Adenocarcinoma, pancreatic ductal adenocarcinoma model, patient response, Patients, Phase I/II Clinical Trial, Positioning Attribute, pre-clinical, Prognosis, Radiation therapy, Reporting, Research, Research Personnel, response, Role, Safety, Signal Transduction, single cell analysis, T cell response, T-Lymphocyte, Testing, Therapeutic, Tissues, TNFRSF5 gene, Translating, Treatment Efficacy, treatment strategy, trial design, tumor, Tumor Antigens, Tumor Immunity, tumor microenvironment, Tumor-Derived, Tumor-infiltrating immune cells, Work | Department of Internal Medicine/Medicine, WASHINGTON UNIVERSITY, Saint Louis, MO 63130, United States |
| 1R21NS123596-01 | Keselowsky, Benjamin George, Schmidt, Christine E (Contact) | Functionalized Enzyme Treatments for Dual-Targeting of Inflammation in Spinal Cord Injury | 2021, funded from 09/01/2021 to 02/28/2023 | PROJECT SUMMARY Unlike other tissues, such as skin and muscle that are capable of complete tissue remodeling, the central nervous system (CNS) lacks the ability to properly heal after injury. Instead, CNS wound repair is marked by sustained glial reactivity and scar tissue deposition, all of which are exacerbated by inflammation. Therapeutic application of the anti-inflammatory methylprednisolone is the only current treatment option for spinal cord injury (SCI), however, it only has acute efficacy and does not resolve tissue remodeling or scarring. This project proposes to investigate idoleamine 2,3-dioxygenase (IDO) as a novel immunomodulatory therapeutic for SCI. IDO is attractive for its dual targeting ability not only to downregulate pro-inflammatory responses but also to promote pro-regenerative cell phenotypes, effectively restoring the imbalance of inflammatory processes after CNS injury. The guiding hypothesis of this research is that IDO will have dual efficacy in immunomodulation of acute systemic inflammation and mitigation of chronic resident cell activation and scarring in the spinal cord. Moreover, the project will investigate two innovative, functionalized forms of IDO for directed targeting of systemic and localized immunomodulation in SCI. First, IDO modified with polyethylene glycol (PEG) will be used for systemic intravenous administration immediately after SCI. PEG improves protein stability in blood and prolongs circulation time, making it an ideal candidate for systemic delivery. PEG-IDO will target circulating leukocytes to modulate early stage inflammation after injury. Secondly, IDO fused with galectin- 3 (Gal3), a glycan binding protein to increase local retention at a tissue target site, will be delivered one week after injury to evaluate effects on resident cell reactivity, reparative immune cell presence, and tissue scarring. The rationale for this design is to better harness IDO?s ability to promote reparative mechanisms in immune cells and glia that are locally present around the lesion site. Co-administration of IDO-Gal3 with key compounds that direct production of neuroprotective metabolites by resident glia (i.e., KMO inhibitors) will further enhance therapeutic effects of localized IDO. Together, this combination will be delivered within a novel, pro-regenerative decellularized neural scaffold to synergistically mitigate neuroinflammation. Overall, the dual immunomodulation potential of IDO provides a new perspective for anti-inflammatory drug administration for CNS injury. The proposed work will demonstrate merit for the individual novel approaches with PEG-IDO and IDO-Gal3 for cell-specific targeting. The long-term goal is to use this mechanistic understanding as a first step in research efforts to develop more effective combination strategies for CNS repair. | National Institute Of Neurological Disorders And Stroke | R21 | Acute, Anti-Inflammatory Agents, Astrocytes, Autoimmune, axon regeneration, Binding, Binding Proteins, Blood, Blood Circulation, Carbohydrates, Cause of Death, Cell Death, Cells, central nervous system injury, Chronic, Cicatrix, Clinical, Complex, cost, Cues, cytokine, Deposition, design, Dioxygenases, disability, Down-Regulation, effective therapy, efficacy testing, Engineering, enzyme therapy, Enzymes, Extracellular Matrix, FDA approved, Feedback, Formulation, Galectin 3, glial activation, Glycosaminoglycans, Goals, Growth, healing, Homeostasis, Hour, Human body, hydrogel scaffold, Hydrogels, Immune, Immune response, Immunomodulators, immunoregulation, improved, Individual, indoleamine, Infiltration, Inflammation, Inflammatory, Inflammatory Response, inhibitor/antagonist, Injectable, Injections, Injury, innovation, Intravenous, intravenous administration, Kynurenine, Lesion, Leukocytes, Liver, macrophage, Methylprednisolone, Microglia, Modification, monocyte, Mus, Muscle, Natural regeneration, Nerve, Neuraxis, Neuroglia, neuroinflammation, neutrophil, novel, novel strategies, novel therapeutics, Pathology, Pathway interactions, Pharmaceutical Preparations, Phenotype, Polyethylene Glycols, Polysaccharides, pre-clinical research, Process, Production, Prognosis, Property, Protein Engineering, Proteins, Psoriasis, public health relevance, Recombinant Proteins, Recombinants, Recovery of Function, regenerative, regenerative cell, Regimen, relating to nervous system, repaired, Reperfusion Injury, Research, response, scaffold, Site, Skin, Spinal Cord, Spinal cord injury, Spinal cord injury patients, Spinal Cord Lesions, standard of care, Steroids, systemic inflammatory response, Target Populations, Therapeutic, Therapeutic Effect, Time, tissue repair, Tissues, Translations, Trauma, Traumatic CNS injury, Tryptophan, Tryptophan 2,3 Dioxygenase, Up-Regulation, Work, wound healing | Department of Biomedical Engineering, UNIVERSITY OF FLORIDA, Gainesville, FL 32611, United States |
| 1K99CA263194-01 | Dang, Fabin | Novel regulation of the CDK4/Cdh1/Pin1 signaling axis for targeted breast cancer therapies | 2021, funded from 07/01/2021 to 06/30/2022 | Project Summary/Abstract: The anaphase-promoting complex/Cyclosome (APC/C) is a well-defined multi-subunit E3 ubiquitin ligase that regulates targeted cell cycle regulators for degradation by the Ubiquitin Proteasome Pathway (UPP), promoting cell cycle progression from metaphase to anaphase and being involved in G1 phase maintenance. The APC/C E3 ligase complex is evolutionarily conserved and relies on two adaptor proteins, Cdc20 and Cdh1, to recognize different target proteins and regulate cell cycle progression. However, compared to Cdc20 that is subjected to Cdh1-mediated destruction, regulation of the E3 ligase activity of Cdh1 is not well known yet. Previous study has shown that there were 19 serine and threonine residues on Cdh1 that can be phosphorylated by multi-kinases in vivo, indicating that the phosphoregulation of Cdh1 is much more complex. In the present proposal, I found that CDK4 can phosphorylates Cdh1 in vitro and modulates its E3 ligase activity. Furthermore, we found that the phosphorylation of Cdh1 by CDK4 can be recognized by the Pin1 proline isomerase, facilitating Cdh1-Pin1 complex formation. In keeping with this notion, employment of the CDK4/6 inhibitor or mutating the phosphorylation sites can disrupt the Cdh1-Pin1 interaction. Consequently, Cdh1 can mediate Pin1 for polyubiquitination and degradation. As such, depletion of endogenous Cdh1 abolished the Pin1 inhibitor treatment induced Pin1 degradation in cells. Importantly, the Pin1 inhibitor-induced cell proliferation suppression was also abolished in Cdh1-null MEFs, suggesting the functional presence of Cdh1 is required for Pin1 inhibitor-induced cell proliferation suppression. In addition, combination of the CDK4/6 inhibitor and Pin1 inhibitor exhibits significantly enhanced suppressing effect in breast cancer cells. In the first Aim of this proposal, I am going to explore the role of CDK4 kinase in regulating the E3 ligase activity of Cdh1 (Aim #1). Therefore, the second Aim in this proposal will be exploring the potential role of Cdh1 in mediating Pin1 inhibitor treatment induced Pin1 protein destruction (Aim 2). Together, these results implicate a functional role of the CDK4/Cdh1/Pin1 signaling axis in regulating cell proliferation, and provide rational for combining the CDK4/6 inhibitor and Pin1 inhibitor to treat breast cancer. | National Cancer Institute | K99 | Adaptor Signaling Protein, Anaphase, anaphase-promoting complex, Breast Cancer Cell, Breast Cancer therapy, breast tumorigenesis, cancer stem cell, cancer therapy, CDK4 gene, Cell Culture Techniques, Cell Cycle, Cell Cycle Arrest, Cell Cycle Progression, Cell Cycle Proteins, Cell Cycle Regulation, Cell Proliferation, Cells, Clinical, Complex, Couples, Cyclin D1, Data, design, Development, Employment, Exhibits, G1 Phase, Genetic, Goals, Human, Immune, In Vitro, in vivo, inhibitor/antagonist, kinase inhibitor, Maintenance, malignant breast neoplasm, Malignant Neoplasms, Mediating, Metaphase, Mitosis, Modeling, Molecular, mouse genetics, multicatalytic endopeptidase complex, Mutate, novel, novel therapeutics, Oncogenic, Oncoproteins, overexpression, Pathway interactions, Peptidylprolyl Isomerase, Phosphorylation, Phosphorylation Site, Phosphotransferases, Physiological, Pin1 protein, Play, Polyubiquitination, prevent, Process, protein degradation, protein expression, protein function, Proteins, RB1 gene, Regulation, response, Role, S Phase, Serine, Signal Transduction, Therapeutic, Therapeutic Effect, Threonine, Tumor Suppressor Proteins, tumorigenesis, Ubiquitin, ubiquitin-protein ligase, Work | BETH ISRAEL DEACONESS MEDICAL CENTER, Boston, MA 02215, United States |
| 1R01HL159062-01 | Kitsis, Richard N | Modulation of Mitofusin Activity to Treat Heart Disease | 2021, funded from 08/01/2021 to 07/31/2022 | Mitochondrial ?connectivity? and mitochondrial-endoplasmic/sarcoplasmic reticulum (ER/SR) ?proximity? each potentiate mitochondrial-mediated metabolism and necrosis through a variety of mechanisms. Mitofusins (MFN) 1 and 2 are large GTPases that play critical roles in mitochondrial connectivity and mitochondrial-ER/SR proximity. MFN1 and MFN2 reside in the outer mitochondrial membrane where they mediate mitochondrial fusion. MFN2, but not MFN1, also resides in the ER/SR membrane, where it tethers ER/SR to mitochondria through interactions with mitochondrial-localized MFN1 or MFN2. Deletion of MFN1 or MFN2 reduces myocardial infarct (MI) size during ischemia/reperfusion (I/R). Conversely, MFN1 and MFN2 overexpression augment metabolism. Given this information, therapeutic inhibition of MFNs would be expected to reduce infarct size during MI, while therapeutic activation of MFNs might attenuate heart failure (HF) by augmenting metabolism. The challenge has been to find a means to manipulate the activities of endogenous MFNs. In collaboration with others, we created the first peptides and small molecules that modulate conformations of MFN1 and MFN2 and delineated the underlying structural basis for these effects. We reported previously that MFN activators increase, while MFN inhibitors decrease, mitochondrial fusion. These are direct effects that require binding of these agents to either MFN1 or MFN2. We present here new data showing that MFN activators increase, while MFN inhibitors decrease, mitochondrial-ER/SR proximity and Ca2+ transfer to mitochondria. Moreover, we observed that MFN activators exacerbate infarct size during myocardial I/R, while MFN inhibitors reduce infarct size in both heart and brain I/R models. Interestingly, these effects of the activators are dependent on MFN2, but not MFN1, suggesting the importance of mitochondrial-ER/SR proximity but not excluding the possibility that MFN2- dependent changes in mitochondrial connectivity and shape also contribute. Additionally, MFN activators promote cardiomyocyte metabolism. The goals of this project are to understand the mechanisms by which MFN modulators impact cardiomyocyte death and metabolism and to test whether these agents might provide novel therapeutic strategies for MI and HF. We propose: 1. To correlate changes in MFN activation/inhibition with mitochondrial connectivity, mitochondrial-ER/SR proximity, Ca2+ transfer, cell death, and metabolism in adult cardiomyocytes. 2. To delineate the individual contributions of mitochondrial connectivity and mitochondrial- ER/SR proximity to cell death and metabolism in cardiomyocytes in vivo. 3. To assess whether mitofusin modulators provide novel therapeutic strategies for MI and HF. This project breaks new ground in defining the mechanisms by which MFN modulators impact cardiomyocyte death and metabolism and whether MFNs provide an actionable target for novel therapies directed against MI and HF. | National Heart, Lung, And Blood Institute | R01 | Adult, Apoptotic, Attenuated, Binding, Brain Ischemia, Cardiac Myocytes, Cell Death, Cells, Cellular Metabolic Process, Cessation of life, Collaborations, Data, Event, experimental study, Family, genetic approach, Goals, Guanosine Triphosphate Phosphohydrolases, Heart Diseases, Heart failure, heart function, heart metabolism, in vivo, Individual, Infarction, inhibitor/antagonist, Ischemia, Knockout Mice, Mediating, Membrane, Metabolism, Mitochondria, mitochondrial metabolism, Modeling, Molecular Conformation, mouse model, Mus, myocardial infarct sizing, Myocardial Infarction, Myocardial Ischemia, Necrosis, new therapeutic target, novel therapeutic intervention, Organelles, Outer Mitochondrial Membrane, overexpression, Peptides, Phenocopy, Play, Proteins, Reperfusion Therapy, Reporting, Respiratory Chain, Role, Sarcoplasmic Reticulum, Shapes, small molecule, Structure, Testing, Therapeutic | ALBERT EINSTEIN COLLEGE OF MEDICINE, Bronx, NY 10461, United States |
| 1R01HL159055-01 | Kim, Jiwon | Cardiac Magnetic Resonance for Tissue Characterization Based Risk Stratification of Cardiopulmonary Symptoms, Effort Tolerance, and Prognosis Among COVID-19 Survivors | 2021, funded from 09/01/2021 to 07/31/2022 | PROJECT SUMMARY / ABSTRACT Coronavirus disease 2019 (COVID-19) is an ongoing global pandemic. Despite substantial short term mortality risk, the overwhelming majority of infected patients survive acute illness, resulting in a growing population at risk for long term events. Cardiopulmonary symptoms are common after COVID-19, as shown by survey data reporting fatigue (53%), dyspnea (43%), and worsened quality of life (44%) 60 days after acute infection, but mechanism and time course of symptoms are unknown. Recent studies and our own preliminary data have shown myocardial tissue abnormalities on cardiac magnetic resonance (CMR) to be common in COVID-19 survivors ? raising the possibility that symptoms stem from viral effects on the heart. However, CMR findings to date are limited by small size and clinical data susceptible to referral bias, raising uncertainty as to generalizability. It is also unknown whether altered myocardial tissue properties (fibrosis, edema) impact clinical outcomes. The central hypothesis of our research is that CMR tissue characterization will be incremental to clinical assessment and cardiac contractile function for prediction of long-term cardiopulmonary symptoms, effort tolerance, and prognosis among COVID-19 survivors. To test this, we will study patients from an active multi- ethnic NYC registry of COVID-19 survivors: We have already leveraged echocardiographic imaging data from this registry to show that (1) adverse cardiac remodeling (dilation, dysfunction) markedly augments short term mortality, (2) COVID-19 acutely alters left and right ventricular remodeling, and (3) many patients who survive initial hospitalization for COVID-19 have adverse cardiac remodeling ? including 40% with left ventricular (LV) dysfunction and 32% with adverse RV remodeling (dilation, dysfunction): Our current proposal will extend logically on our preliminary data to test whether CMR tissue characterization provides incremental predictive utility with respect to reverse remodeling and prognosis. At least 510 COVID-19 survivors will be studied. Echo will be analyzed at time of and following COVID-19 for longitudinal remodeling, as will CMR at pre-specified (6- 12, 36 month) follow-up timepoints. Established and novel CMR technologies will be employed, including assessment of cardiac and lung injury, high resolution (3D) myocardial tissue characterization, and cardiopulmonary blood oxygenation. In parallel, QOL, effort tolerance (6-minute walk test), biomarkers, and rigorous follow-up will be obtained to discern clinical implications and relative utility of imaging findings. Aim 1 will identify determinants of impaired quality of life and effort intolerance among COVID-19 survivors. Aim 2 will test whether myocardial tissue injury on CMR is associated with impaired contractility, and whether fibrosis predicts contractile recovery. Aim 3 will determine whether myocardial tissue injury is independently associated with adverse prognosis (new onset clinical heart failure, hospitalization, mortality). Results will address key knowledge gaps regarding COVID-19 effects on the heart necessary to guide surveillance, risk stratification, and targeted therapies for millions of COVID-19 survivors at risk for myocardial injury, cardiopulmonary symptoms, and adverse prognosis. | National Heart, Lung, And Blood Institute | R01 | 3-Dimensional, Acute, acute infection, Address, adverse outcome, Affect, Arrhythmia, base, Biological Markers, Blood, Cardiac, Cardiopulmonary, Chest Pain, Clinical, Clinical assessments, clinical biomarkers, Clinical Data, clinical predictors, clinically relevant, common symptom, coronary fibrosis, COVID-19, COVID-19 patient, Data, data registry, Data Reporting, Dyspnea, Echocardiography, Edema, Event, Fatigue, Fibrosis, follow-up, Functional disorder, functional status, General Population, Heart, Heart failure, Heart Injuries, Heart Research, Histopathology, Hospitalization, Image, Impairment, improved, indexing, Infection, Inflammation, Knowledge, Left, Left Ventricular Dysfunction, Longterm Follow-up, Lung, Lung diseases, lung injury, Magnetic Resonance, Magnetic Resonance Imaging, Measures, Methods, mortality, mortality risk, multi-ethnic, Myocardial dysfunction, myocardial injury, Myocardial tissue, Myocardium, New York City, novel, Outcome, pandemic disease, Patients, Physiological, Population, Populations at Risk, predict clinical outcome, Prognosis, Property, Pulmonary Pathology, Quality of life, Recovery, Registries, Reporting, Research, Resolution, response, Right Ventricular Dysfunction, Risk, risk stratification, Specific qualifier value, stem, Structure, study population, Surveys, Survivors, Symptoms, targeted treatment, Technology, Testing, therapy development, Thrombosis, Time, tissue injury, Tissues, Treatment Failure, Uncertainty, United States, Ventricular, Ventricular Remodeling, Viral, Walking | Department of Internal Medicine/Medicine, WEILL MEDICAL COLL OF CORNELL UNIV, New York, NY 10065, United States |
| 1UG3DE030869-01 | Lee, Sue Ann Soyoung | Speech Intervention via Telepractice for Children with Repaired Cleft Palate : Randomized Controlled Trial and Assessment of Speech Production and Perception Skills | 2021, funded from 09/09/2021 to 08/31/2022 | PROJECT SUMMARY/ABSTRACT Although the Individuals with Disabilities Education Act (IDEA) ensures that all children with disabilities are provided with appropriate public education, there is an increasing inequity in the provision of speech- language services across the U.S. due to the critical shortage of speech-language pathologists (SLPs) in public school settings. Telepractice is one way to mitigate the shortage issue. Currently available telepractice studies have been conducted with small sample sizes and varying methodological rigor. In particular, to date no treatment efficacy studies via telepractice have been conducted on children with a history of cleft palate (CP). Children with repaired CP often develop compensatory articulation patterns which are not common in children with speech disorders. It is imperative to identify whether telepractice is efficacious for children with repaired CP to treat compensatory articulation. In evaluation of compensatory articulation errors, two major limitations exist in the current literature. First, these errors are mainly examined based on the listener's auditory-perceptual judgement without instrumental analysis; second, how speech perception plays a role in production of compensatory articulation has not been fully investigated although ample evidence suggests interplay between perception and production skills. As a Phase I randomized controlled trial (RCT), this proposal responds to the NIDCR Behavioral Social Intervention Clinical Trial Planning & Implementation Cooperative Agreement (UG3/UH3). This proposal fits with NIDCR's Strategic Plan in that it aims to develop and test an effective behavioral intervention for children with oral and craniofacial disorders. Our aim during the UG3 one-year planning period is to (1) finalize the intervention protocols, (2) develop the Manual of Operations, (3) develop custom software for the data management system, and (4) stimuli and software development for the speech perception experiment in order to complete an unbiased RCT design for the UH3 phase. Our primary aims during the UH3 phase are (Aim 1) to establish the efficacy of telepractice speech intervention for children with repaired CP, and (Aim 2) to quantitatively define compensatory articulation errors using instrumentation analyses, and (Aim 3) to determine speech perception deficits in children with CP. This research will be clinically significant because Aim 1 will assist clinicians to make evidence-based decisions to adopt a telepractice service delivery model to treat children with repaired CP. Aims 2-3 will provide important clinical rationales to evaluate speech production using instrumental analyses and to identify speech perception deficits when clinicians treat children with CP. The importance of this study is highlighted by the current COVID-19 pandemic. The associated social-distancing restrictions have been imposed upon school teachers and SLPs to adopt telepractice while continuing to provide educational and therapeutic services. Thus, the results of the proposed study will meet an increasing demand for telepractice efficacy studies for children with speech disorders. | National Institute Of Dental & Craniofacial Research | UG3 | acoustic imaging, Acoustics, Adopted, Affect, Agreement, Articulation, Auditory, base, Behavior, Behavior Therapy, Behavioral, Characteristics, Child, Cleft Palate, Clinical, Clinical Trials, clinically significant, Communication, Computer software, control trial, COVID-19 pandemic, craniofacial disorder, Custom, Data, Data Management Resources, Development, Disabled Children, Disabled Persons, Education, Effectiveness, efficacy research, efficacy study, efficacy testing, Emotional, Ensure, Evaluation, evidence base, executive function, experimental study, functional outcomes, Genetic Transcription, glottis, Goals, health care service, Healthcare, improved, Individual, innovation, instrumentation, Intervention, intervention program, Intervention Studies, Judgment, Language, language impairment, Literature, Manuals, Measures, Methodology, Methods, Mission, Modeling, Monitor, Mouth Diseases, National Institute of Dental and Craniofacial Research, operation, Output, Parents, Pathologist, Patients, Pattern, Perception, Pharyngeal structure, Phase, Physiological, Play, Population, Process, Production, programs, Protocols documentation, public education, Randomized, Randomized Controlled Trials, Recording of previous events, repaired, Reporting, Research, Role, rural area, Safety, Sample Size, School Teachers, School-Age Population, Schools, Self-control as a personality trait, service delivery, Service delivery model, Services, Severities, skills, social, Social Distance, social interventions, software development, Speech, Speech Disorders, Speech Perception, Stimulus, Strategic Planning, Technology, Testing, Therapeutic, Time, treatment effect, Treatment Efficacy, Treatment outcome, Treatment Protocols, trial comparing, trial design, U-Series Cooperative Agreements, underserved rural area, United States, United States National Institutes of Health, urban area | TEXAS TECH UNIVERSITY HEALTH SCIS CENTER, Lubbock, TX 79430, United States |
| 1R01DA054312-01 | Hudson, Teresa Jo, Thompson, Joseph W (Contact) | Population-Based Analyses of Healthcare Utilization and Outcomes in Users of Medical Marijuana | 2021, funded from 09/30/2021 to 07/31/2022 | PROJECT SUMMARY Limited scientific consensus exists on the clinical, healthcare system, financial, or societal impact of legalization of medical marijuana (MMJ) in states. The swift changes in state policies regarding MMJ use, combined with the current national opioid epidemic, creates an impending need to better understand the clinical, pharmacological, and behavioral impact of MMJ. The state of Arkansas approved MMJ use in 2016 by individuals with select conditions, and dispensaries opened in May 2019. Unique data assets available through the Arkansas Healthcare Transparency Initiative and the Arkansas Health Data Initiative (HDI) consist of individually linked but de-identified mandatory all-payer claims, vital statistics, hospital and emergency department (ED) discharge, and state police motor vehicular crash data, along with data on individuals who qualify for MMJ use. This will be the first population-level analysis that measures clinical and adverse events in a population of MMJ users and non-users through three specific aims: Specific Aim 1: Describe demographic, geographic, socioeconomic, and clinical characteristics; healthcare utilization, adverse events (new mental health diagnoses, substance abuse/overdose, suicide, accidental injury, or MVA accidents); and opioid and benzodiazepine use among three groups: 1) individuals eligible for MMJ in Arkansas who do not obtain an MMJ card (non-cardholders) , 2) individuals who are eligible and obtain a MMJ card but do not purchase MMJ (cardholders), and 3) those who are eligible, obtain a card, and purchase MMJ (consumers). Specific Aim 2: Compare 12-month pre- and post-healthcare use and costs (inpatient and outpatient care, ED visits, and prescription medications), and adverse events between consumers and non-cardholders. As a sub-aim, we will evaluate changes in opioid and benzodiazepine utilization after commencing a course of MMJ therapy. Specific Aim 3: Examine the impact of COVID-19 on MMJ cardholder requests, MMJ purchases, healthcare use, and adverse events. This project brings together five data sources to examine the impact of MMJ on Arkansans. This includes the Arkansas All Payer Claims Database (APCD), the MMJ registry, vital statistics files, and data documenting emergency department visits and MVAs. These data are linkable at the person level which allows person-level analyses or healthcare utilization and outcomes. This will be the first population-level analysis that measures clinical and adverse events in a population of MMJ users and non-users. Results of this research will help fill the gap in scientific knowledge by determining whether MMJ use has benefits (e.g, decreased healthcare use and cost, substitution opioids and benzodiazepines) while producing no additional harm (e.g., new mental health diagnosis, MVAs) and thus inform future MMJ policy. | National Institute On Drug Abuse | R01 | Accident and Emergency department, Accidental Injury, Accidents, Address, Admission activity, Adverse event, adverse outcome, Affect, Ambulatory Care, American, Anxiety, Arkansas, Behavioral, Benefits and Risks, Benzodiazepines, Cannabis, care outcomes, Cessation of life, Characteristics, chronic pain, Clinical, clinical care, Clinical Decision Support Systems, Clinical Pharmacology, cohort, Consensus, Consumption, cost, cost outcomes, COVID-19, Data, Data Sources, Databases, Diagnosis, Dose, Drug Prescriptions, Emergency department visit, Engineering, Epilepsy, Future, Geography, Glaucoma, Goals, Guidelines, Health, Health Care Costs, health care service utilization, health data, Health Policy, Healthcare, Healthcare Systems, Hospital Departments, Individual, innovation, inpatient service, insurance claims, interest, Intervention, Investigation, Knowledge, Legal, Link, Marijuana, marijuana use, marijuana user, Measures, Medical, Medical Informatics, Medical Marijuana, Medical Records, Medicine, Mental disorders, Mental Health, mortality, Motor, Multiple Sclerosis, Opioid, opioid epidemic, Opioid Rotation, opioid use, Outcome, Outcome Study, Overdose, Patients, Persons, Pharmaceutical Preparations, Physicians, Police, Policies, Population, population based, population health, Population Research, Post-Traumatic Stress Disorders, practice setting, public health research, reduce symptoms, Registries, Research, response, socioeconomics, Source, Substance abuse problem, Suicide, symposium, THC concentration, Ulcerative Colitis, United States National Academy of Sciences, Vehicle crash, vehicular accident, Vital Statistics | Department of Internal Medicine/Medicine, UNIV OF ARKANSAS FOR MED SCIS, Little Rock, AR 72205, United States |
| 1R01NS123116-01 | Bikoff, Jay Benjamin | Interneuron circuits in the spinal motor system | 2021, funded from 05/15/2021 to 04/30/2022 | Project Summary: Neural circuits in the spinal cord serve as the conduit through which the nervous system controls muscle contraction to implement behavior. Defining spinal circuit organization is therefore central to understanding the neural control of movement. One major challenge in resolving how spinal circuits direct motor output is the highly heterogeneous nature of spinal interneurons, which shape fundamental elements of limb movement underlying locomotion and skilled forelimb behaviors. Because our ability to resolve distinct interneuron cell types remains limited, little is known about the synaptic and circuit organization of spinal interneurons or their functional contributions to motor output. We recently discovered that spinal V1 interneurons, the largest inhibitory interneuron population in the spinal motor system, constitute a molecularly heterogeneous group that can be segregated into at least four mutually exclusive subsets (clades) defined by expression of the transcription factors Foxp2, MafA, Pou6f2, and Sp8. V1 clades exhibit restricted and highly stereotyped positions in the spinal cord, and several show distinct electrophysiological signatures. As such, V1 interneurons represent an ideal system in which to explore general principles of interneuron identity and circuitry governing motor output, of relevance to other classes of spinal interneurons. Motivated by our discovery of V1 interneuron diversity, this proposal aims to (1) define the molecular and cellular identity of these clades and the mechanisms through which this diversity arises, (2) test the hypothesis that descending motor pathways from the brain differentially innervate V1 clades, and (3) investigate how V1 interneurons influence one key aspect of motor control ? the speed of rhythmic locomotor output. Together, the proposed experiments address a fundamental gap in knowledge about the identity, circuit organization, and function of interneurons in the spinal motor system, and serve as a foundation for future efforts aimed at dissecting the contributions of specific interneuron cell types to motor behavior, of relevance for developmental motor disorders and spinal cord injury. | National Institute Of Neurological Disorders And Stroke | R01 | Acute, Address, Adolescent, Adult, base, Behavior, Brain, brain pathway, cell type, Data, Development, disability, Electrophysiology (science), Elements, Embryo, Exhibits, experimental study, Forelimb, Foundations, FOXP2 gene, Future, Gene Expression, Genetic, Goals, Interneuron function, Interneurons, Knowledge, limb movement, Limb structure, Link, Locomotion, Logic, Mediating, Methods, Molecular, Motor, motor behavior, motor control, motor disorder, motor impairment, Motor Neurons, Motor output, Motor Pathways, Movement, Mus, Muscle Contraction, mutant, Mutant Strains Mice, Nature, Neonatal, Nervous System control, neural circuit, Neurodegenerative Disorders, Neurons, neuroregulation, novel therapeutic intervention, Output, Pathway interactions, Periodicity, Physiological, Play, Population, Positioning Attribute, programs, Rabies, reconstruction, Research, Role, selective expression, Series, Shapes, Spatial Distribution, Speed, Spinal, Spinal Cord, Spinal cord injury, Stereotyping, System, Testing, transcription factor, Transgenic Organisms, Trauma, Viral | ST. JUDE CHILDREN'S RESEARCH HOSPITAL, Memphis, TN 38105, United States |
| 1R01NS123735-01 | Maricq, Andres Villu | Peptidergic Modulation of NMDA-Receptor Mediated Neurotransmission | 2021, funded from 07/15/2021 to 05/31/2022 | Synapses control information processing by the nervous system, and dysfunction of synapses is associated with many neurological diseases and neurodegenerative disorders. In all nervous systems, glutamate is the primary excitatory neurotransmitter used to activate neurons. The goals of this study are to provide important, new mechanistic insights into the function of glutamatergic synapses, which will aid in our understanding of information processing by the brain and provide new avenues for the development of pharmaceutical therapies for nervous system disorders. Using a genetic platform based on the nervous system of the model organism C. elegans, we will study how peptide ligands, which signal via G-protein coupled receptors, regulate synaptic function mediated by NMDA-type ionotropic glutamate receptors (NMDARs). Synaptic NMDARs are involved in the pathophysiology of numerous psychiatric and neurological disorders. We propose an integrated multidisciplinary approach that combines in vivo electrophysiological analysis, behavioral studies and optogenetic to study the mechanism of action by which specific neuropeptides regulate NMDAR-mediated synaptic signaling. These studies have particular promise for a deeper understanding of nervous system plasticity, and behaviors such as learning and memory. Our studies will reveal new targets for the development of new drugs and novel therapeutic strategies for disorders of nervous system function. | National Institute Of Neurological Disorders And Stroke | R01 | Address, Alzheimer's Disease, Animal Model, Attention, base, Behavior, Behavioral, behavioral phenotyping, behavioral study, Brain, Caenorhabditis elegans, Cell model, Cells, Characteristics, Confocal Microscopy, Defect, Dependence, Development, Disease, Electrophysiology (science), experimental study, Functional disorder, G-Protein-Coupled Receptors, Genes, Genetic, Glutamate Receptor, glutamatergic signaling, Glutamates, Goals, in vivo, information processing, insight, interdisciplinary approach, Interneurons, Intervention, Lead, Learning, Ligands, Link, Locomotion, loss of function, loss of function mutation, Measures, Mediating, Memory, Memory Loss, Mental disorders, Modality, Modeling, Molecular, mutant, N-Methyl-D-Aspartate Receptors, N-Methylaspartate, nervous system disorder, nervous system disorder therapy, Nervous System Physiology, Nervous system structure, Neurodegenerative Disorders, Neurologic, Neuromodulator, neuron loss, Neurons, Neuropeptide Receptor, Neuropeptides, neurotransmission, Neurotransmitters, new therapeutic target, novel therapeutic intervention, novel therapeutics, optogenetics, Peptides, Pharmacologic Substance, Pharmacology, Phenocopy, Physiological Processes, Pigments, postsynaptic, presynaptic, presynaptic neurons, Process, Production, Proteins, receptor, Research, Role, Signal Pathway, Signal Transduction, Synapses, synaptic function, Synaptic Transmission, System, Techniques, Testing, Therapeutic Intervention, Time | Department of Neurosciences, UNIVERSITY OF UTAH, Salt Lake City, UT 84112, United States |
| 1R01EB031893-01 | Green, Alexander Arthur, Wang, Xiao (Contact) | Model-guided design of RNA stabilizing elements for improved coronavirus diagnostics | 2021, funded from 09/17/2021 to 09/16/2025 | Project Summary Fast, inexpensive, and sensitive methods to detect the SARS-CoV-2 coronavirus are instrumental in containing the spread of COVID-19. Currently, nucleic acid testing of respiratory samples using RT-PCR is the primary and most commonly used method for diagnosing patients in the acute phase of the infection. However, this standard approach suffers from the need for special equipment and well-trained personnel and hence has become a bottleneck to meet the urgent demand for large-scale screening. A range of new RNA-based technologies, including toehold switches and CRISPR/Cas systems, are being actively developed with the aim to implement diagnostic tests that are ultra-sensitive, easy to deploy, and make use of enzymes and reagents separate from the traditional PCR pipeline. One common and critical component of these methods is the engineering of RNA molecules to detect target viral sequences. Consequently, their performance in terms of specificity and sensitivity have been significantly hindered by the fast degradation of RNAs caused by the RNases ubiquitous in both clinical sample matrices and as byproducts of biomolecular reagent production. Here we propose to enhance coronavirus diagnostic performance by programming RNase resistance into assay components, in turn increasing RNA stability and enhancing test sensitivity and speed. We will rationally design RNA 5? UTR sequences and the resulting secondary structures of mRNA, toehold switch RNA, and CRISPR guide RNAs to modulate their resistance to RNase activities and hence quantitatively tune their stability. Results from the proposed forward engineering studies will increase our understanding and control of RNA dynamics and provide a widely applicable strategy to improve coronavirus detection efficiencies of many technologies under development. Impact: A comprehensively studied RNA design scheme to improve RNA stability will be complementary to current technologies under development to give them a boost in performance, and provide underlying design strategies with potential broader applicability, such as overcoming the stability barrier for mRNA-based vaccines. There are three specific aims in this proposal: Aim 1: Characterize and model the role of 5? secondary structures in fine-tuning mRNA stability; Aim 2: Optimize sensing RNAs for detection of COVID-19; Aim 3: Use dtRNAs to enhance sample and amplified RNA stability for improved diagnostics. | National Institute Of Biomedical Imaging And Bioengineering | R01 | 5' Untranslated Regions, Acute, aptamer, base, Binding, Biological Assay, Characteristics, Clinical, Clustered Regularly Interspaced Short Palindromic Repeats, Coronavirus, COVID detection, COVID diagnostic, COVID-19, COVID-19 detection, COVID-19 diagnostic, deep learning, design, Detection, detection assay, detection sensitivity, Development, Diagnosis, Diagnostic, diagnostic assay, diagnostic technologies, Diagnostic tests, Elements, Engineering, Enzymes, Guide RNA, Half-Life, Human Resources, improved, In Vitro, Infection, Lead, Libraries, Messenger RNA, Methods, Modeling, mRNA Stability, Norovirus, Nucleic Acid Amplification Tests, Nucleotides, Outcome, Patients, Performance, Phase, portability, preservation, Production, protein expression, Reagent, Reporter, Repression, Resistance, respiratory, Reverse Transcriptase Polymerase Chain Reaction, Ribonucleases, RNA, RNA amplification, RNA Degradation, RNA Stability, RNA vaccine, role model, Sampling, Scheme, screening, Sensitivity and Specificity, sensor, Special Equipment, Speed, stem, Structure, Technology, Testing, Training, Transcript, Translations, Viral, viral detection | ARIZONA STATE UNIVERSITY-TEMPE CAMPUS, Tempe, AZ 85287, United States |
| 1R01CA262758-01 | Kurtz, Stephen E, Tyner, Jeffrey Wallace (Contact) | Mechanisms of venetoclax combination activity in acute myeloid leukemia | 2021, funded from 06/02/2021 to 05/31/2022 | PROJECT SUMMARY/ABSTRACT Acute myeloid leukemia (AML) is one of the most common hematologic malignancies, representing a diverse collection of complex diseases. After 30-40 years without change of treatment strategy, the past 2 years have seen several drug approvals, including the most recent approval for the BCL2 inhibitor, venetoclax, used in combination with hypomethylating agents. While response rates of 60-80% with this combination are encouraging, the 1-year survival rate is still only at 30-40%. For the past decade, we have executed a functional genomics platform applied directly to primary samples from patients with AML and other hematologic malignancies. Using this platform, we have collectively studied over 2,500 primary patient specimens, and we have included a series of venetoclax combinations on this platform for the past five years. From this dataset, we have identified several novel venetoclax combinations with better activity than venetoclax plus hypomethylating agents, and we have started a clinical trial for one of the most promising of these combinations, venetoclax with the JAK inhibitor ruxolitinib. For this project, our long-term goals are to optimize and translate the most effective venetoclax drug combinations into the clinic for patients with AML. Our immediate goals are to understand the specific biology driving venetoclax combination synergy and identify biomarkers and mechanisms of response. Based on the central hypothesis that venetoclax combinations exhibit patterns and mechanisms of sensitivity and resistance that are specific to cell differentiation states and transcriptional programs. To accomplish these goals, 3 Aims are proposed: 1) Cell differentiation state as a mechanism of drug combination sensitivity and resistance ? We will perform analytics of cell differentiation state in our large patient sample dataset as well as laboratory models of forced differentiation in cell lines and patient samples. 2) Synthetic lethality as a guide to mechanisms of drug combination sensitivity and resistance ? Our preliminary data from genome-wide CRISPR/Cas screens point to specific candidate genes that impact on mediators of venetoclax combination activity. These candidates will be explored with genetic and pharmacologic perturbations. 3) Clinical validation of biomarkers and mechanisms of sensitivity and resistance ? We have opened a clinical trial testing venetoclax combined with ruxolitinib in AML. We will have access to longitudinal specimens from patients on this trial. We will perform ex vivo drug testing on these trial specimens coupled with transcriptional and proteomic studies to evaluate the ability of each data type to predict clinical responses. Cumulatively, we expect these innovative analyses to have a major impact on our understanding of AML biology, with successful clinical translation of new, more effective drug combination strategies. | National Cancer Institute | R01 | Acute Myelocytic Leukemia, acute myeloid leukemia cell, Automobile Driving, Azacitidine, base, BCL2 gene, biobank, Biological Markers, Biology, biomarker validation, Blinded, Candidate Disease Gene, Cell Differentiation process, Cell Line, Cells, chemotherapy, Clinic, Clinical, clinical biomarkers, clinical predictors, clinical translation, clinical trial analysis, Clinical Trials, Clustered Regularly Interspaced Short Palindromic Repeats, Collection, Complex, Computer Models, Coupled, CRISPR screen, Data, Data Set, Dendritic Cells, Disease, Dropout, Drug Approval, Drug Combinations, drug sensitivity, Drug Targeting, drug testing, Effectiveness, Elderly Acute Myeloblastic Leukemia, Enrollment, Enzymes, Evaluation, Event, Exhibits, FDA approved, FLT3 gene, functional genomics, Genes, Genetic, Genetic Transcription, genome-wide, Genomic approach, genomic data, genomic platform, Goals, Hematologic Neoplasms, Immunophenotyping, Incentives, inhibitor/antagonist, innovation, insight, knockout gene, Laboratories, macrophage, Mediating, Mediator of activation protein, Modeling, monocyte, Mutate, Mutation, Myelogenous, neoplastic cell, novel, novel therapeutics, Outcome, Pathway interactions, patient population, Patients, Pattern, Pharmacology, Population, pre-clinical, predicting response, programs, Progression-Free Survivals, prospective, Proteomics, Refractory, Relapse, Research Personnel, Resistance, resistance mechanism, response, response biomarker, Sampling, screening, Series, Signal Transduction, Specimen, Survival Rate, synergism, Testing, TP53 gene, transcriptome sequencing, Translating, treatment strategy, tumor, Undifferentiated, Validation, Work | Department of Internal Medicine/Medicine, OREGON HEALTH & SCIENCE UNIVERSITY, Portland, OR 97239, United States |
| 1R01DA054190-01 | Ciccarone, Daniel H | Synthetics in Combination (SYNC) | 2021, funded from 09/30/2021 to 06/30/2022 | Summary Over the last decade fentanyls, methamphetamine and benzodiazepines have proliferated in US illicit drug markets. These synthetic drugs, increasingly in combinations, are implicated in the ongoing rise in overdose fatalities. Although drug overdoses commonly involve more than one substance, polydrug use has long been understudied. Now, the replacement of heroin with novel synthetics such as fentanyls, the resurgence of methamphetamine, and the proliferation of counterfeit pills, have created a situation of new complexity and unknown risks with an urgent need for knowledge. People who use drugs are creating new patterns and modes of polydrug use, for which their motives and influences are yet to be understood. Some polydrug use may be unintentional due to contamination or counterfeit products. For example, the contamination or co-use of methamphetamine with fentanyls may explain the recent rise in stimulant-related mortality. Examination of the use of the once rare but resurgently popular methamphetamine and heroin cocktail, aka `goofball', now remodeled with fentanyl, may give clues to the salience and rationale of polysynthetics in drug use repertoires as well as their adverse outcomes. Aim 1 (Ethnography): To elucidate the effects of synthetic drug supply changes (primarily fentanyls and methamphetamine) on people who use drugs in combination and to understand their preferences for and responses and adaptations to these changes. Aim 2 (Epidemiology): To examine the shift towards polysynthetic drug use through studies of local and national drug supply and health outcome databases and to determine a) the roles of unintentional co-use from cross-contamination and counterfeit pharmaceuticals, intentional co-use and drug price/purity/potency in patterns of synthetic polydrug use and b) the morbidity and mortality outcomes of these use patterns. Aim 3 (Modeling): To forecast overdose mortality based on evolving risk and protective factors from synthetic drug combinations. We will use mechanistic (agent-based modeling) and statistical predictive modeling tools, accounting for the effects of different modes of administration (smoking vs injecting), adaptation (eg tester shots) and interventions (eg naloxone). The Synthetics in Combination (SYNC) study will integrate micro-to-macro-level anthropological, economic, epidemiological and modeling approaches to gain insight into polydrug use on the ground, to measure and predict both adverse effects and model methods of mitigating harm. Achieving its objectives will advance understanding of drug epidemics and morbidities, help tailor public health interventions and provide community level tools for better monitoring and allocation of scarce resources. | National Institute On Drug Abuse | R01 | Accounting, Address, Adverse effects, adverse outcome, analog, Anthropology, base, Benzodiazepines, Cessation of life, Communities, Data, Data Analyses, Databases, design, Drug Combinations, drug market, Drug usage, Drug user, Economics, Environment, Epidemic, epidemiological model, Epidemiology, Ethnography, Fentanyl, Health, Heroin, high risk, high risk population, Hospitalization, Illicit Drugs, Injections, innovation, insight, Intervention, Interview, Investments, Knowledge, Measures, Methamphetamine, methamphetamine use, Methods, Modeling, Monitor, Morbidity - disease rate, mortality, multiple drug use, Naloxone, novel, Opioid, opioid epidemic, opioid overdose, Outcome, Outcome Study, Overdose, overdose death, Pattern, Peer Review, Pharmaceutical Preparations, Pharmacologic Substance, pill, Play, predictive modeling, preference, prescription opioid, Price, Proliferating, protective factors, Public Health, public health intervention, Research, Resources, response, Review Literature, Risk, Risk Factors, Role, Shapes, Smoking, Study models, synthetic drug, synthetic opioid, Techniques, tool, Youth | Department of Family Medicine, UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, San Francisco, CA 94143, United States |
| 1R01AG073480-01 | Bookheimer, Susan Y | Modulation of Hippocampal Circuitry and Memory Function with Focused Ultrasound in Amnestic MCI | 2021, funded from 08/15/2021 to 07/31/2022 | ABSTRACT For patients with mild cognitive impairment (MCI) and Alzheimer?s Disease (AD) there are few effective treatments for memory enhancement. Strategies that directly manipulate neural activity are promising but currently have serious limitations. Deep brain stimulation (DBS) of the entorhinal cortex (ERc), a part of the brain important for memory, in a small sample of patients has been shown to improve memory, but DBS is highly invasive and requires neurosurgery. Other neuromodulation techniques that do not require surgery are limited in that they target only surface brain structures. In MCI and AD, it is the deep brain structures, including the ERc and the hippocampus (HC) that are most affected. Low intensity focused ultrasound pulsation (LIFUP) uses acoustic energy waves with frequencies higher than humans can hear to penetrate the skull to effect specifically targeted deep brain regions. Therefore, LIFUP could be targeted at the deep brain structures critical for episodic memory formation, the same regions that are affected in MCI and AD. We are the first to do just this and our preliminary data shows that LIFUP: increases perfusion of the ERc; increased functional connectivity of the ERc/HC memory network and may improve behavioral memory performance. Our LIFUP set-up is safe to use inside a magnetic resonance imaging (MRI) machine which allows for simultaneous brain modulation and real- time measurement of the modulation using MRI. We will use each participant?s structural brain MRI to aim LIFUP at the ERc. This will allow us to directly test the effects of LIFUP on activity in the ERc, in other brain regions connected to the ERc (e.g. HC), as well as on blood flow in the HC and other brain areas important for memory. Applying this to patients with MCI, we will try to determine the dose, booster effect and duration of LIFUP effects on brain and blood flow, structure and function, determine whether these LIFUP-related changes improve memory in this population and evaluate the effect of LIFUP on blood-based biomarkers of AD-related neurodegeneration. Understanding how the parameters of LIFUP dose and booster session effect the impact and duration of LIFUP on brain, biomarker and memory performance will be a significant step towards constructing a comprehensive clinical trial. The ability to change the activity and blood flow of brain regions by targeting them with LIFUP would be an important step towards developing a non-invasive memory prosthetic that would make a very significant contribution to AD treatment. | National Institute On Aging | R01 | Acoustics, Affect, Alzheimer associated neurodegeneration, Alzheimer's Disease, Alzheimer's disease pathology, Alzheimer?s disease biomarker, amnestic mild cognitive impairment, Anterior, Area, base, behavior measurement, Behavioral, Biological Markers, Blood, Blood flow, blood-based biomarker, Brain, Brain region, Cerebrovascular Circulation, Clinical, Clinical Trials, cranium, Data, Deep Brain Stimulation, Devices, Diagnosis, Dose, Double-Blind Method, effective therapy, entorhinal cortex, Episodic memory, Focused Ultrasound, follow-up, Frequencies, Functional Magnetic Resonance Imaging, healthy aging, Hearing, Hippocampus (Brain), Human, improved, Learning, Magnetic Resonance Imaging, Measures, Memory, mild cognitive impairment, Morphology, multimodality, neuroimaging, Neuropsychology, neuroregulation, neurosurgery, Operative Surgical Procedures, Participant, Patients, Performance, Perfusion, Phase, Physiologic pulse, Population, Prosthesis, Randomized, relating to nervous system, Rest, Sampling, Site, Structure, Surface, Techniques, temporal measurement, Testing, Thick, Time, Treatment outcome, Ultrasonography, Up-Regulation, white matter | Department of Psychiatry, UNIVERSITY OF CALIFORNIA LOS ANGELES, Los Angeles, CA 90095, United States |
| 3R01EB026344-03S1 | Hammond, Paula T | Multivalent Nano-conjugates for Targeted Penetration of and Delivery to Dense Extracellular Matrices | 2021, funded from 03/11/2021 to 05/31/2021 | Although nanoparticles have been found to be effective in delivery to more traditional vascularized organs and tissues, there are different challenges for nanoparticle transport in tissues that lack a vascular system to assist in penetration into the tissue. Here we propose a systematic approach to the design of nanomaterials systems that are capable of deep penetration and delivery of agents into avascular tissues. The proposed work will focus on establishing sets of materials design concepts to enhance transport into and through these tissues based on size, charge density and presentation, targeting and dynamic materials chemistries. In the Aim 1, we will develop two promising families of multivalent drug nanocarriers with modular design, each presenting unique advantages for tissue penetration. The transport of these nanocarriers will then be examined as a function of size and charge using ex vivo tissue models to rapidly screen libraries of nanocarriers and identify optimal size/charge characteristics for tissues of interest. We will examine transport in three unique avascular tissue types: cartilage, meniscus and cornea to understand similarities or differences in design requirements and optimal transport characteristics for a range of avascular tissue types. Further translation of this Aim is anticipated to provide fundamental knowledge regarding how to address other similar barrier tissues in the context of drug delivery. Treatment of cartilage to address conditions such as osteoarthritis presents a particularly important medical challenge, and is the disease focus for the later Aims of these studies; however, successful demonstration of this system in the first Aim will be applicable to other tissues and conditions, including delivery to the cornea and joint meniscus. To enable a more tissue-responsive delivery approach, both pH responsive and enzyme degradable linkers will be examined in Aim 2 for the conjugation of therapeutics, with the focus on conjugation of IGF-1, a growth factor that can facilitate cartilage regeneration in early stage osteoarthritis. Optimized versions of the nanocarriers will be studied in an established in vivo using an early surgical trauma rat model to evaluate the efficacy of IGF-1 treatments with the nondegradable, hydrolytic, and protease-activated degradable linkers and determine in vivo real-time pharmacokinetics versus free IGF-1. Cartilage treatment studies will be carried out in this model for IGF-1 delivery. Finally, an additional aspect of this study will be the design of nanoconjugates that release drug selectively to regions of tissue matched to the different nanocarrier transport properties determined in earlier Aims, including degree of penetration and residence time within the tissue. Combination treatments for small molecule drugs including dexamethasone and TLR4 inhibitors will be conjugated to carriers optimal for each drug, in combination with the top IGF-1 formulation. We will evaluate the therapeutic effects of the combinations in a cytokine-challenged ex vivo cartilage tissue model by measuring inflammatory markers, matrix deposition and maintenance, and kinetics of cartilage repair. 1 | National Institute Of Biomedical Imaging And Bioengineering | R01 | ADAMTS, Address, Anatomy, animal imaging, animal tissue, Anti-Inflammatory Agents, base, Binding, Biodistribution, Biological, Blood Vessels, Cartilage, cartilage regeneration, cartilage repair, Cathepsins, Cell Culture Techniques, Characteristics, Charge, chemical function, Chemistry, clinical biomarkers, Conjugated Carrier, Cornea, crosslink, cytokine, Degenerative polyarthritis, density, Deposition, design, Dexamethasone, Diagnostic, Disease, Drug Combinations, Drug Delivery Systems, Drug Kinetics, Drug Targeting, effective therapy, Electrostatics, Enzyme-Linked Immunosorbent Assay, Enzymes, Exhibits, experimental study, Extracellular Matrix, Extravasation, Family, Fluorescence Resonance Energy Transfer, Formulation, Generations, Growth Factor, Heart, Hemolysis, Histology, Hydrolysis, Image, imaging agent, imaging facilities, Immunohistochemistry, In Vitro, in vivo, Inflammatory, inflammatory marker, Inflammatory Response, inhibitor/antagonist, Insulin-Like Growth Factor I, interest, joint inflammation, Joints, Kinetics, Knowledge, Label, Libraries, Ligaments, Liver, Lung, Maintenance, Matrix Metalloproteinases, Measures, Medical, Meniscus structure of joint, Modeling, Molecular Analysis, nanocarrier, Nanoconjugate, nanomaterials, nanomedicine, nanoparticle, Operative Surgical Procedures, Organ, Oryctolagus cuniculus, particle, Penetration, Peptide Hydrolases, Peptides, Pharmaceutical Preparations, Positron-Emission Tomography, Process, Property, Radiolabeled, Rattus, repaired, residence, Serum, small molecule, Solid Neoplasm, Surface, System, Tendon structure, Testing, Therapeutic, Therapeutic Effect, therapeutic evaluation, Time, Tissue Model, Tissues, TLR4 gene, Toxic effect, Toxicology, trafficking, transcriptome sequencing, Translations, Trauma, uptake, Vascular System, Work | Department of Engineering (All Types), MASSACHUSETTS INSTITUTE OF TECHNOLOGY, Cambridge, MA 02142, United States |
| 1R43DP006690-01 | Mcgeorge, Nicolette | ART Provider and Patient Resource to Improve Communication about Outcomes and Treatment (APRICOT) | 2021, funded from 09/30/2021 to 09/29/2022 | Project Summary/Abstract Infertility affects an estimated 8-12% of reproductive-aged couples, leading many to seek assisted reproductive technologies (ART) treatments such as in vitro fertilization (IVF), gamete intrafallopian transfer (GIFT), and zygote intrafallopian transfer (ZIFT). Approximately 1.9% of infants born in the United States each year are conceived using ART. The Fertility Clinic Success Rate and Certification Act (FCSRCA) of 1992 mandates that clinics performing ART treatment annually report success rate data to the Centers for Disease Control and Prevention (CDC); however, clinics face challenges in collecting accurate pregnancy outcome information from these patients or the patients' new healthcare providers. To collect pregnancy outcomes, ART clinics rely on traditional outreach methods, including telephone, mail, and email, to obtain information from patients, who may be out of state or even country, and their obstetric providers. This process requires significant effort, often requiring multiple attempts. However, collecting this information is important because the CDC uses ART surveillance data to monitor the success rates of treatments performed in the U.S. and to characterize the short- and long-term health effects of ART on patients and infants conceived after ART treatments. To improve the response rates and data quality while reducing per patient costs, Charles River Analytics and our collaborator, Dr. Shruthi Mahalingaiah from Massachusetts General Hospital, propose to design and evaluate an ART Provider and Patient Resource to Improve Communication about Outcomes and Treatment (APRICOT). APRICOT is a health information technology (HIT) application to alleviate the burden on assisted reproductive technology (ART) clinics associated with collecting pregnancy outcomes from prior ART patients and the patients' other healthcare providers. Under this Phase I effort, we will use human factors engineering methods, including qualitative research methods, contextual design, and user acceptance testing, to elicit clinic and patient user requirements, design candidate workflows and user interfaces, and demonstrate the feasibility of developing APRICOT. Our effort will establish ART clinic and patient user requirements and produce conceptual designs for a pregnancy outcome reporting platform that facilitates streamlined communication between ART clinics and their patients. APRICOT will enable fertility clinics to collect pregnancy outcome information efficiently and effectively from prior ART patients and the patients' other healthcare providers. APRICOT will assist clinics in meeting federally mandated reporting requirements by reducing the effort required of clinic staff to collect pregnancy outcome information from previous ART patients and their obstetric providers, helping clinics to realize time and monetary cost savings in collecting pregnancy outcomes from prior patients. | National Center For Chronic Disease Prev And Health Promo | R43 | CHARLES RIVER ANALYTICS, INC., Cambridge, MA 02138, United States |
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