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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 | ||
|---|---|---|---|---|---|---|---|---|
| 1R01HL158718-01 | Wolf, Matthew J | DYRK1a as a therapeutic target to treat myocardial infarction | 2021, funded from 08/15/2021 to 07/31/2022 | ABSTRACT Although outcomes after myocardial infarctions (MIs) have improved, cardiomyocytes (CMs) are lost even with successful reperfusion. This loss contributes to adverse remodeling, ischemic cardiomyopathy, heart failure, arrhythmia, and death. Current therapies can only slow or reverse isolated aspects of ischemic heart disease, and there are no reliable therapies available to replace the cardiac muscle loss to MI. Identifying therapeutic targets and drugs to protect the myocardium after injury will be groundbreaking, address unmet clinical needs, and represent new strategies to treat cardiovascular diseases. Our goals are to identify and validate druggable targets that induce controlled CM cycling and improve heart function after injury. However, two challenges exist: (1) the identification of candidate pathways to stimulate CM cycling with the intent to improve cardiac function after injury, and (2) the accurate quantification of CM cycling events in adult myocardium. Therefore, we conducted investigations to address the two challenges. First, we identified an inhibitor of dual-specificity tyrosine phosphorylation-regulated kinase 1a (DYRK1a), Harmine, increased CM cycling, and improved ventricular function after MI. Next, we generated CM-specific DYRK1a knockout mice and observed CM hyperplasia at baseline and improved LV function after MI, suggesting DYRK1a contributes to CM function. Second, we designed and validated a unique transgenic mouse (denoted ?DKRC) that drives Cre in adult cycling CMs. ?DKRC complements existing technologies such as Mosaic Analysis with Double Markers (MADM); however, the ability to restrict Cre expression to adult cycling CMs is an advance in the field. We used ?DKRC::DTA mice to express Diphtheria toxin in adult cycling CMs and observed that the loss of endogenously cycling CMs worsened myocardial function after MI. Since cycling CMs are scarce, the findings suggest that cycling CMs may contribute to myocardial function beyond the concept of a CM as only a contractile cell, perhaps by expressing paracrine factors. This potential mechanism suggests that modest increases in cycling CMs may have a more significant impact on cardiac function after MI because cycling CMs serve functions beyond the concept of contractility. Based on preliminary data, we hypothesize that the inhibition of DYRK1a improves myocardial function after MI, in part, through enhanced CM cycling and the cycling CMs exert their effects via paracrine factors. We will test our hypothesis in the following Aims: (1) The CM-specific ablation of DYRK1a during development protects LV function after MI through enhanced cell cycling, (2) The post- developmental ablation of DYRK1a in adult CMs will improve LV function after MI, and (3) Cycling CMs contribute to LV function after MI by expressing paracrine factors. The proposed investigations will define the potential of DYRK1a inhibition as a treatment of MI, identify the mechanisms through which DYRK1a exerts its effects in CMs, and characterize novel paracrine factors expressed by cycling CMs that potentially serve as new future therapeutic targets. | National Heart, Lung, And Blood Institute | R01 | Ablation, Address, Adult, Apoptosis, Arrhythmia, base, Blood capillaries, candidate identification, Cardiac Myocytes, Cardiovascular Diseases, Cell Cycle, Cells, Cessation of life, Clinical, Complement, Data, density, design, Development, Diphtheria Toxin, druggable target, event cycle, functional improvement, Future, Genetic, Goals, Harmine, Heart, Heart failure, heart function, Hyperplasia, improved, improved outcome, Infarction, inhibitor/antagonist, Injury, Investigation, Ischemia, ischemic cardiomyopathy, kinase inhibitor, Knock-out, Knockout Mice, Left Ventricular Function, Left Ventricular Remodeling, Morbidity - disease rate, mortality, Mosaicism, Mus, Muscular Atrophy, Myocardial, Myocardial Infarction, Myocardial Ischemia, Myocardial Reperfusion, Myocardium, Neonatal, novel, Outcome, paracrine, Pathway interactions, Pharmaceutical Preparations, Pharmacology, Phosphotransferases, Regenerative capacity, Reperfusion Therapy, Reporter, Ribosomal Proteins, RiboTag, secretory protein, Signal Pathway, Signal Transduction, Societies, Specificity, Technology, Testing, therapeutic target, Transcript, Transgenic Mice, Tyrosine Phosphorylation, Ventricular Function, Work | Department of Internal Medicine/Medicine, UNIVERSITY OF VIRGINIA, Charlottesville, VA 22904, United States |
| 1K23DK129770-01 | Wang, Hao | Macrovascular and Microvascular Response to Fluid Removal during Hemodialysis for Acute Kidney Injury | 2021, funded from 07/01/2021 to 04/30/2022 | Project Summary Over 13 million people develop acute kidney injury (AKI) each year. AKI increases the risk of incident chronic kidney disease, end-stage kidney disease, and death. Fluid removal (ultrafiltration) is an important component of managing dialysis-requiring AKI (AKI-D), but safe achievement of optimal volume status involves a delicate balance between preventing fluid overload and avoiding circulatory compromise. Acuity of illness and comorbid conditions render patients with AKI highly susceptible to even modest hemodynamic changes, and routine blood pressure monitoring may be inadequate to detect subtle, yet clinically meaningful, perfusion changes during hemodialysis. Continuous monitoring of systemic or local tissue perfusion is feasible using a variety of near-infrared optical technologies, but there has been limited application of these devices during hemodialysis particularly in the setting of AKI. The overarching premise of this proposal is that optimizing fluid management in an already vulnerable AKI population requires (1) a marker that captures an individualized hemodynamic response to fluid removal throughout hemodialysis treatments, and (2) more sensitive techniques to detect hypoperfusion. Funded by an F32 award, Dr. Wang previously leveraged continuous hematocrit monitoring (CHM) during maintenance hemodialysis treatments to calculate a semi-instantaneous plasma refill rate (PRR), which refers to the rate of refilling of the vascular space from the interstitial space during ultrafiltration. Through this K23 proposal, Dr. Wang will extend her investigations of PRR to the AKI setting and will evaluate novel approaches to assessing perfusion during hemodialysis. Specifically, Dr. Wang will perform mediation analysis using data from a large cohort of patients on maintenance hemodialysis to determine whether PRR mediates the effects of treatment-related factors on intradialytic hypotension (Aim 1); and, in a prospective cohort of patients with AKI-D, she will combine continuous hematocrit monitoring with two noninvasive techniques ? diffuse correlation spectroscopy and diffuse optic spectroscopy ? to simultaneously measure changes in systemic perfusion (Aim 2) and cerebral perfusion and oxygenation (Aim 3) as a novel approach to elucidate the physiology underlying both overt and subtle hemodynamic effects of hemodialysis. Additionally, she will use bedside testing to link spatiotemporal changes in tissue physiology with changes in cognitive function. To conduct this work, Dr. Wang will utilize the formal methodologic training and practical experience in epidemiology, study design, and longitudinal analysis that she acquired through the Master of Science in Clinical Epidemiology Program. Through her K23 career development plan, she will gain (1) skills in designing and implementing prospective studies in dialysis, (2) experience studying outcomes in acute care, and (3) expertise in advanced methods for analyzing multidimensional data. Upon completion of this work, Dr. Wang will be well-positioned to obtain R01 funding to continue working toward her long-term goal of developing novel approaches that will increase the precision of renal replacement therapy and improve patient outcomes. | National Institute Of Diabetes And Digestive And Kidney Diseases | K23 | Achievement, acute care, Acute Renal Failure with Renal Papillary Necrosis, Advanced Development, Adverse effects, adverse outcome, Affect, Age, Attention, Award, Bedside Testings, Blood Pressure Monitors, Blood Vessels, Cardiac Output, career development, cerebral oxygenation, Cerebrovascular Circulation, Cerebrum, Cessation of life, Chronic Kidney Failure, Clinical, clinical epidemiology, cognitive function, cognitive testing, cohort, Cohort Studies, comorbidity, Complex, Complication, Critical Illness, Data, Data Set, Degree program, design, Development, Development Plans, Devices, Dialysis procedure, Diffuse, End stage renal failure, Epidemiologic Methods, epidemiology study, Equilibrium, Excision, experience, Fluid overload, Functional disorder, Funding, Goals, heart function, Hematocrit procedure, Hemodialysis, hemodynamics, Homeostasis, Hybrids, hypoperfusion, Hypotension, Impairment, improved, Inpatients, Institution, Intensive Care Units, interstitial, Intervention Studies, Investigation, Ischemia, Kidney, Life, Linear Regressions, Link, Liquid substance, longitudinal analysis, Maintenance, Master of Science, Measurement, Measures, Mediating, Mediation, Mediator of activation protein, Mentors, Methodology, Methods, Modality, Modeling, Monitor, multidimensional data, multidisciplinary, multiple chronic conditions, Myocardial Stunning, novel strategies, Observational Study, Operative Surgical Procedures, Optics, Organ, Outcome, Outcome Study, Outpatients, Oxygen, Participant, Patient-Focused Outcomes, Patients, Perfusion, personalized approach, Physiology, Plasma, Population, Positioning Attribute, Postoperative Period, pressure, prevent, programs, prospective, Prospective cohort, Prospective cohort study, Prospective Studies, rate of change, Reaction Time, Recovery, Renal dialysis, Renal Replacement Therapy, Research Design, Research Personnel, response, Risk, skills, spatiotemporal, Spectrum Analysis, Statistical Models, System, Techniques, Technology, Testing, Tissues, Trail Making Test, Training, treatment effect, Treatment Factor, Ultrafiltration, Venous, vigilance, Work | Department of Internal Medicine/Medicine, UNIVERSITY OF PENNSYLVANIA, Philadelphia, PA 19104, United States |
| 1R21HD105880-01 | Krishnan, Mohan Kumar | RBC TRANSFUSION IN ANEMIC NEONATES LEADS TO SYSTEMIC INFLAMMATORY RESPONSE SYNDROME | 2021, funded from 08/06/2021 to 07/31/2022 | Project summary Transfusions of Red Blood Cells (RBCT) are necessary and life-saving in premature and critically ill infants, who experience severe anemia due to both physiologic and iatrogenic factors. Recently, we have shown that severe anemia was associated with increased intestinal permeability, demonstrated by the identification of endotoxin in the bloodstream. Additionally, there is increasing recognition of the dangers of the necessary step of blood bank storage prior to transfusion. Transfusions of stored RBCs are rapidly cleared by liver macrophages, producing non-transferrin bound iron (NTBI) to circulate in plasma, acutely inducing inflammation through iron deposition in tissues. The risks of experiencing severe anemia during critical developmental periods must be balanced with the risks of transfusions, which can lead to Systemic Inflammatory Response Syndrome (SIRS) and potentially Multi Organ Dysfunction Syndrome (MODS). The underlying mechanism(s) by which anemia and transfusion directly or indirectly correlate with the development of SIRS remain unclear. Critical evaluation of the association between RBC transfusion and SIRS is necessary to improve clinical practice and develop therapeutic strategies to prevent and/or ameliorate anemia-RBCT associated SIRS. To investigate RBCT associated SIRS, the investigators used an existing murine model in which 10-day-old mouse pups were subjected to timed phlebotomy between postnatal days (P) 2-10 to induce severe anemia (hematocrits 18%-22%), at which point they received an intravenous RBC transfusion, then observed for up to 24h. Based on preliminary data, the investigators propose a novel hypothesis that anemic neonates are uniquely predisposed to SIRS because of direct transmigration of bacterial products from the hypoxic intestine due to loss of intestinal barrier function, facilitating the hepatic monocyte response with preformed cytokines; RBCT can potentiate this effect. There are two specific aims: (1) Determine the pathophysiological role of neonatal liver (NL)-derived monocytes in the development of SIRS during anemia and RBC transfusion. (2) Determine whether blocking trem1 activity on liver monocyte and/or restoration of anemia-associated intestinal permeability can prevent/ameliorate anemia-transfusion associated SIRS. Accomplishment of the proposed aims will explain the mechanisms and potential strategies to prevent and/or treat anemia-RBCT transfusion associated SIRS in critically-ill neonates. | Eunice Kennedy Shriver National Institute Of Child Health & Human Development | R21 | Acute, Address, Adult, Anemia, Attenuated, Bacterial Translocation, base, Biological, Blood, Blood Banks, Blood Circulation, Bone Marrow, clinical practice, critical developmental period, Critical Illness, cytokine, cytokine release syndrome, Data, Deposition, Development, Endotoxins, Erythrocyte Transfusion, Erythrocytes, Evaluation, Exocytosis, experience, Fetus, Functional disorder, Funding Opportunities, Hematocrit procedure, Hematopoiesis, Heme, Hemin, Hepatic, Hour, Human, Iatrogenesis, improved, In Situ, in vivo, Infant, Inflammation, Inflammatory, Inflammatory Response, inhibitor/antagonist, insight, intestinal barrier, intestinal hypoxia, Intestinal permeability, Intravenous, Investigation, Iron, ITGAM gene, kinase inhibitor, Knowledge, Kupffer Cells, Lead, Leukocytes, Life, Lipopolysaccharides, Liver, macrophage, monocyte, mouse model, Mus, Myelogenous, Myeloid Cells, Myosin Light Chain Kinase, Neonatal, Neonatal Anemia, neonatal mice, neonate, novel, Organ, Peptides, Physiological, Plasma, Population, Portal vein structure, postnatal, pre-clinical, Pregnancy, premature, preterm newborn, prevent, Production, pup, receptor, Research Personnel, response, restoration, Risk, Role, Savings, Severities, Site, Source, Spleen, Surface, Syndrome, Systemic Inflammatory Response Syndrome, Testing, Therapeutic, therapeutically effective, Tissues, Transfusion, uptake, Venous blood sampling | Department of Pediatrics, JOHNS HOPKINS UNIVERSITY, Baltimore, MD 21218, United States |
| 1R35GM142749-01 | Miller, Matthew P | Mechanical activities ensuring accurate chromosome segregation | 2021, funded from 08/01/2021 to 05/31/2022 | PROJECT SUMMARY / ABSTRACT: A central aspect of cell division is the faithful segregation of chromosomes. Errors in chromosome segregation are the leading cause of miscarriages, and are associated with the vast majority of tumor cells. Despite this, we know very little about why this process is so defective in these circumstances, in large part because the molecules and mechanisms involved are not fully defined. A highly conserved protein complex, the kinetochore, physically attaches chromosomes to the spindle microtubules that are central to pulling chromosomes apart every time a cell divides. Doing this accurately requires kinetochores to remain persistently attached to a constantly changing substrate, the dynamically growing and shrinking tips of the spindle microtubules. They must also sense when they?re improperly attached and self-correct these errors. How kinetochores carry out these dynamic functions remains largely mysterious. We propose to investigate two key aspects of the kinetochore- microtubule interface. First, we know that the ability to sense tension (mechano-sensing) is vital for monitoring erroneous attachments of chromosomes to the spindle. Yet, how mechanical forces are sensed by and transmitted through this megadalton protein assembly is poorly understood. Second, the kinetochore?s ability to specifically recognize and bind to various microtubule tip structures is also crucial. How the microtubule side of this interface impacts kinetochore attachment fidelity is unknown, and has remained largely unstudied. Understanding these critical questions has proven challenging because of the lack of ways to measure and manipulate the kinetochore?s highly dynamic activities. Prior studies utilized mainly genetic and cell biological approaches, relying on downstream functional readouts that do not directly monitor protein activity. We use an innovative and fundamentally different strategy, combining cutting-edge biochemical and biophysical tools to reconstitute the activities of these protein machines in vitro. The ability to reconstitute these activities allows us to examine both sides of this interface, making our approach uniquely capable of addressing these fundamental questions in innovative ways. Capitalizing on my groundwork in which I identified the first factor, Stu2chTOG, required for a novel mechano-sensing pathway, we have now determined its exact kinetochore binding site via structural analysis and developed genetic tools allowing us to perturb and inducibly re-localize it to kinetochores. We will use these tools to expand insight into the mechanisms of mechano-sensing and extend our knowledge of the factors involved. We will also examine which kinetochore activities are affected by alterations to its microtubule substrate. We have identified numerous tubulin mutations that specifically disrupt chromosome segregation, and our reconstitution-based assays now give us the unique ability to understand this mechanistically. This approach constitutes the first direct examination of the microtubule side of this interface. I anticipate this work will greatly increase our understanding of how kinetochores work to segregate chromosomes and how defects arise in human disease. | National Institute Of General Medical Sciences | R35 | Address, Affect, base, Binding, Binding Sites, biochemical tools, Biological, Biological Assay, biophysical tools, Cell division, Cells, Chromosome abnormality, Chromosome Segregation, Chromosomes, Congenital Abnormality, Defect, Ensure, fitness, Genetic, Human, human disease, In Vitro, innovation, insight, Kinetochores, Knowledge, Lead, Malignant Neoplasms, Measures, mechanical force, Mechanics, mechanotransduction, Mediating, Microtubules, Molecular, Monitor, Mutation, neoplastic cell, novel, Pathway interactions, Process, protein complex, Proteins, reconstitution, segregation, Side, Spontaneous abortion, Structure, Time, tool, Tubulin, Work | Department of Biochemistry, UNIVERSITY OF UTAH, Salt Lake City, UT 84112, United States |
| 1R35GM142750-01 | Robustelli, Paul | Characterizing the binding mechanisms of castration-resistant prostate cancer therapeutics to the intrinsically disordered N-terminal domain of the androgen receptor | 2021, funded from 09/15/2021 to 06/30/2022 | Project Summary /Abstract Intrinsically disordered proteins (IDPs), which lack a fixed three-dimensional structure under physiological conditions, represent ~40% of the human proteome, have crucial functional roles in a variety of biological pathways and biomolecular assemblies and are implicated in a large number of human diseases. As IDPs populate a dynamic conformational ensemble of rapidly interconverting structures in solution, and cannot be represented by a single dominant conformation, or even a small number of substantially populated conformations, they are not suitable targets for conventional structure-based drug design methods. If it becomes possible to target IDPs with small molecule drugs, the druggable proteome will be dramatically expanded and therapeutic interventions may become accessible for currently untreatable diseases The PI?s laboratory utilizes an integrated computational and experimental research strategy to combine state-of-the-art all-atom molecular simulations with experimental measurements from NMR spectroscopy and other biophysical experiments to obtain atomistic descriptions of the dynamic binding mechanisms of IDPs and uses insights form these binding mechanisms to predict and rationally design novel binding interactions. This proposal focuses on applying this integrated computational and experimental approach to elucidate the binding mechanisms of small molecule drug candidates that target that intrinsically disordered domain of the androgen receptor and have entered clinical trials for castration resistant prostate cancer (CRPC). These binding mechanisms will be used to inform the rational design more potent and selective androgen receptor inhibitors and more effective CRPC therapeutics . This proposal describes a remarkable opportunity to draw connections between molecular binding mechanisms studied by molecular simulations and NMR, biological activity observed in cellular assays, and clinical results from human CRPC drug trials. This proposal will initiate a sustainable long-term research effort to combine computational and experimental methods to study the dynamic interactions of IDPs in a variety of cellular and pharmaceutical contexts. This research effort will stimulate the development of robust platforms to integrate computational and experimental methods that will dramatically increase the number of proteins amenable to structural and mechanistic characterization and pharmaceutical targeting and will provide new avenues to therapeutic interventions in diseases associated with aberrant biological interactions of IDPs such as those mediated by biomolecular condensate formation and protein misfolding. | National Institute Of General Medical Sciences | R35 | Androgen Receptor, Antineoplastic Agents, base, Binding, Biological, Biophysics, castration resistant prostate cancer, Cellular Assay, Clinical, Clinical Trials, design, Development, Disease, drug candidate, Drug Design, Drug Targeting, experimental study, Human, human disease, inhibitor/antagonist, insight, Laboratories, Measurement, Mediating, Methods, Molecular, Molecular Conformation, N-terminal, NMR Spectroscopy, novel, Pathway interactions, Pharmaceutical Preparations, Pharmacologic Substance, Physiological, protein misfolding, Proteins, Proteome, Research, Role, simulation, small molecule, Structure, Therapeutic, Therapeutic Intervention, therapeutic target, three dimensional structure, Work | Department of Chemistry, DARTMOUTH COLLEGE, Hanover, NH 03755, United States |
| 1R01EY032882-01 | Lin, Phoebe | Intestinal T cells and microbiota as therapeutic targets in autoimmune uveitis | 2021, funded from 09/01/2021 to 06/30/2022 | Project Summary Chronic autoimmune uveitis represents a medical management conundrum, which left untreated, is a significant cause of blindness in the US and worldwide. Yet due to an incomplete understanding of its pathogenesis, treatment has often required use of non-specific anti-inflammatory agents that can have untoward side effects. Emerging evidence links the intestinal microbiota to extraintestinal autoimmune diseases like uveitis, providing new clues into pathogenesis, and novel avenues for therapeutic targeting. Our goal is to investigate how the intestinal microbiota can be manipulated to re-establish intestinal and thus systemic immune homeostasis that has gone awry during the course of autoimmune uveitis. To do this, we are using a quintessential T-cell mediated model, experimental autoimmune uveitis (EAU). We will utilize two different interventions to alter the intestinal microbiota, antibiotics and short chain fatty acid (SCFA) metabolites of intestinal bacterial fermentation of dietary fiber, in EAU. Enhancement of intestinal Tregs (cells that usually suppress the immune system) by these microbiota-altering interventions will be tested by adoptive transfer of Tregs and in vitro Treg suppression assays. The impact of microbiota-altering interventions on intestinal immune cell migration to peripheral lymphoid tissues and the eye during EAU will also be investigated. Direct microbiota effects on enhancement of intestinal Treg abundance and uveitis severity will be tested by fecal microbial transplantation from antibiotic or SCFA-pre-treated animals. These results are expected to yield novel insights into autoimmune uveitis pathogenesis as well as lay groundwork for new treatment strategies targeting the intestinal microbiota to re-establish immune homeostasis. | National Eye Institute | R01 | Address, Adoptive Transfer, Affect, Animals, Anti-Inflammatory Agents, Antibiotics, Arthritis, Autoimmune Diseases, autoimmune uveitis, Bacteria, Biological Assay, Biological Markers, Blindness, Body part, cell motility, cell type, Cells, Chronic, Dietary Fiber, Disease, Disease Pathway, drinking water, effector T cell, Equilibrium, Eye, fecal transplantation, Fermentation, Frequencies, Goals, gut microbiota, Homeostasis, Immune, Immune system, Immunity, Immunophenotyping, improved, In Vitro, in vivo, Inflammation, Inflammatory, inflammatory disease of the intestine, insight, Intervention, intestinal barrier, intestinal epithelium, intestinal homeostasis, Intestinal permeability, Intestines, Left, Link, Lymphoid Tissue, Measures, Mediating, Medical, Metronidazole, microbial, microbiota, microorganism, migration, Modeling, Morphology, mouse model, Mus, new therapeutic target, novel, novel strategies, Pathogenesis, Peripheral, prevent, Production, Propionates, protective effect, Proteins, Regulatory T-Lymphocyte, Severities, side effect, T-Lymphocyte, Testing, therapeutic target, Time, trafficking, Transgenic Organisms, treatment strategy, Uveitis, Volatile Fatty Acids | Department of Ophthalmology, OREGON HEALTH & SCIENCE UNIVERSITY, Portland, OR 97239, United States |
| 1R01DK129307-01 | Pate, Russell R | Understanding Community Obesity Initiatives and Informing Tailored Community Interventions to Reduce Childhood Obesity | 2021, funded from 09/01/2021 to 06/30/2022 | Childhood obesity rates in the United States increased dramatically between the 1980?s and the 2000?s and remain high in all demographic sub-groups. The rates are particularly high in African American and Hispanic children. In response to these trends and following the recommendations of leading health authorities, many U.S. communities have implemented programs and policies aimed at improving children?s diets, increasing their physical activity levels, and reducing childhood obesity. However, the impact of these efforts has been limited, and neither research nor professional practice has yet identified the attributes of community programs and policies that are consistently successful in improving children?s diet, increasing their physical activity, and decreasing the probability that they will develop overweight or obesity. The overarching goal of the proposed research is to produce findings that inform public health policies and practices aimed at reducing disparities in the prevalence of childhood obesity. Specific aims will be to identify attributes of community programs and policies that are associated with children?s diet, physical activity and weight status within groups of communities, schools, and families stratified by race/ethnicity and socioeconomic status. These aims will be addressed by conducting secondary analyses in an existing dataset that includes in-depth observations of a diverse sample of over 5000 children and assessment of over 9500 community programs and policies to reduce childhood obesity in 130 U.S. communities. Further, within those communities, extensive data on school nutrition and physical activity policies, practices and resources are available for 274 elementary and 149 middle schools. A home-based data collection protocol provided anthropometric data as well as detailed information on children?s diet and physical activity behaviors. Two analytic methods, Classification and Regression Trees (CART) and Gradient Boosting Machines (GBM), will be employed in examining relationships between attributes of community programs and policies and children?s diet, physical activity and weight status. These analytic procedures will be conducted within sub-groups of communities, schools and families stratified by race/ethnicity and socioeconomic status profiles. The findings of the proposed study will enable researchers and practitioners to tailor community-based interventions to the characteristics of demographic sub-groups. This research will be significant because it will inform strategies for preventing childhood obesity in communities and population sub-groups that are disproportionately affected by the negative consequences of obesity. The study will be innovative because it will apply state-of-the-art analytical methods using a dataset that is uniquely large and comprehensive. | National Institute Of Diabetes And Digestive And Kidney Diseases | R01 | Address, Adolescent, African American, Age, Agreement, analytical method, authority, base, Behavior, Characteristics, Child, classification trees, Communities, community based participatory research, community intervention, Consensus, Data, Data Collection, Data Set, Diet, disparity reduction, Eating, Ethnic Origin, excessive weight gain, experience, Family, Goals, Health, health disparity, Health Policy, Health Promotion, Hispanics, Home, improved, innovation, Intervention, junior high school, Methodology, negative affect, next generation, nutrition, Obesity, obesity in children, obesity treatment, Overweight, Physical activity, Policies, Population, Poverty, Prevalence, prevent, Preventive service, Primary Prevention, Probability, Procedures, Professional Practice, programs, Protocols documentation, Public Health, Race, Recommendation, regression trees, Research, Research Personnel, Resources, response, Risk, Sampling, Schools, secondary analysis, sex, social culture, Socioeconomic Status, socioeconomics, Students, Subgroup, success, trend, United States, Weight | Department of Other Health Professions, UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA, Columbia, SC 29208, United States |
| 1R56HL158803-01 | Girotra, Saket | Peripheral Artery Disease: Long-term Survival & Outcomes Study (PEARLS) | 2021, funded from 09/20/2021 to 08/31/2022 | Project Summary/Abstract Background: Peripheral artery disease (PAD) is a common and highly morbid condition. Nearly 25% of patients die within 3 years of diagnosis, likely due to a high incidence of cardiovascular (CV) events: myocardial infarction (MI) or stroke. A significantly larger proportion experience disability due to leg pain, poor mobility and amputation. The cost of PAD-related hospital care alone exceeds $21 billion. However, research regarding long-term survival, CV, and limb outcomes in PAD and the impact of existing treatments remain limited in large part due to the poor accuracy of PAD diagnosis codes. Our team has developed a novel approach using natural language processing (NLP) to identify PAD patients with a high degree of accuracy within the Veterans Health Administration (VHA). Significance: The Peripheral Artery Disease: Long-term Survival & Outcomes Study (PEARLS) study will advance scientific knowledge for PAD in several ways. We will use our NLP tool to assemble one of the largest cohorts of PAD in the world and follow them long-term to assess the trajectory of survival and clinical outcomes, evaluate utilization of recommended treatments (medications, risk factor control and revascularization) and the association of above treatments with the above outcomes. Collectively, our work will address important gaps in PAD research and yield insights regarding strategies to improve care delivery in this high-risk population. Innovation: The use of an informatics-based method to assemble a cohort of newly diagnosed PAD patients in a large integrated health system is highly innovative. We believe that our approach for cohort identification will be transformational and promote big data analytics for research, improving care delivery, and future clinical trials. Specific Aims: A1. Develop a national cohort of Veterans with newly diagnosed PAD using a novel NLP algorithm. A2. Examine patterns of medical and invasive management and determine patient- and facility-level correlates. A3. Determine the impact of medical and invasive management of PAD on long-term outcomes. Methodology: We will implement our NLP algorithm to identify patients with new PAD diagnosis in VHA during 2015-2020 and obtain data on clinical and treatment related variables. We will follow our cohort longitudinally for mortality, CV events (MI, stroke) and limb events (amputation). We will examine utilization of PAD treatments and risk factor control, identify patient-level and hospital-level predictors of treatment using multi-level models. We will use discrete survival models to evaluate the association of PAD treatments with long-term outcomes. Implementation/Next Steps: Key deliverables will include a) an understanding of which patient groups are at greatest risk for mortality and adverse outcomes; (b) determining the relative impact of PAD treatments on long- term outcomes which can be useful for decision-making and c) an assessment of site-level variation in treatment patterns. We envision that our findings will help us develop comprehensive disease management program to improve quality of care and reduce disparities in use of effective treatments. | National Heart, Lung, And Blood Institute | R56 | Address, adverse outcome, Algorithms, American, Amputation, Ankle, Arteries, base, Big Data, Big Data Methods, Biometry, Blood flow, Blood Pressure, Blood Vessels, Cardiology, Cardiovascular system, care delivery, care outcomes, Caring, Cessation of life, Chronic Care, Chronic Disease, Clinical, Clinical Data, Clinical Practice Guideline, Clinical Treatment, Clinical Trials, Code, cohort, comorbidity, Coronary Arteriosclerosis, cost, critical limb Ischemia, Data, Data Element, Decision Making, Diabetes Mellitus, Diagnosis, disability, discrete data, disease diagnosis, Disease Management, Disease Outcome, disparity reduction, effective therapy, Electronic Health Record, Epidemiology, ethnic minority population, Ethnic Origin, Event, experience, Face, Funding, Future, glycemic control, Glycosylated hemoglobin A, Guidelines, Health system, high risk, high risk population, Hospitals, improved, Incidence, Income, indexing, Informatics, innovation, insight, Integrated Health Care Systems, International Classification of Disease Codes, Kidney Failure, Knowledge, Laboratories, Leg, Life Style, limb amputation, Limb structure, Longitudinal cohort, Low income, Machine Learning, Measures, Medical, Methodology, Methods, Modeling, mortality, mortality risk, multilevel analysis, Myocardial Infarction, Natural Language Processing, Newly Diagnosed, novel, novel strategies, Operative Surgical Procedures, Outcome, Outcome Study, Pain in lower limb, patient subsets, Patient-Focused Outcomes, Patients, Pattern, Peripheral arterial disease, Pharmaceutical Preparations, Predictive Value, Primary Health Care, programs, Quality of Care, Race, Reporting, Research, Risk, Risk Factors, Science, Scientific Advances and Accomplishments, Severities, Site, Specificity, Stroke, stroke event, survival outcome, Symptoms, Testing, time use, Toes, tool, Treatment Factor, United States, Variant, Veterans, Veterans Health Administration, Work | Department of Internal Medicine/Medicine, UNIVERSITY OF IOWA, Iowa City, IA 52242, United States |
| 1R35GM142849-01 | Smukowski Heil, Caitlin Suzanne | Recombination rate variation and evolution | 2021, funded from 08/01/2021 to 05/31/2022 | Abstract Meiotic recombination is necessary for the proper segregation of chromosomes during meiosis, and in creating genetic diversity in populations through the shuffling of alleles. Changes in the number of recombination events, or recombination rate, can thus have impacts on individual organismal health via meiotic failure, and on population fitness by influencing the efficacy of selection. And yet, variation in recombination rate has been documented across the genome, and among populations and species. Despite progress in cataloguing recombination rate variation, how and why recombination rate changes remains largely unknown. The goal of my research program is to investigate the genetic and environmental causes of recombination rate variation, and the consequences of recombination rate variation on genome evolution. Over the next five years, my lab will use experimental evolution and genomics in Saccharomyces yeast to explore three main questions. First, how does the recombination landscape change over short time scales? We are using whole genome sequencing to construct genome wide recombination rates in multiple populations of Saccharomyces uvarum. We seek to identify how the double strand breaks that initiate recombination are repaired as crossover or non-crossover gene conversion events, and how these two types of events are conserved or divergent between populations. This will be the first study to examine evolution in both types of recombination events in multiple populations, offering an unprecedented view of the mechanism underlying recombination rate variation. Second, we are investigating how adaptation to a new environment alters recombination rate. Recombination rate plasticity has been linked to changes in temperature and other environmental factors for many years, but explicit tests of environmental adaptation influencing recombination rate evolution (or vice versa) are missing. We will evolve cold tolerant S. uvarum populations in the lab for increased thermotolerance, and use whole genome sequencing to identify any shifts in recombination rate or the distribution of crossover and non-crossover gene conversion events that occur as a result of adaptation to temperature. Finally, we?re exploring how recombination rate influences the distribution and persistence of introgression in the genome following hybridization. We are evolving admixed strains from 2 diverging populations of S. uvarum with partial reproductive isolation to test the hypothesis that introgression is reduced in regions of low recombination due to selection against weak, negative epistatic interactions. We?ll compare the distribution of introgression in evolved populations to recombination maps to better understand what forces shape genomes in the generations after hybridization. Overall, my research will leverage the benefits of working with the tractable Saccharomyces system to empirically test longstanding hypotheses of how and why recombination changes over time. | National Institute Of General Medical Sciences | R35 | Alleles, Aneuploidy, Biological Models, Cataloging, Chromosome Segregation, Environment, environmental adaptation, Environmental Monitoring, Environmental Risk Factor, Event, Evolution, Failure, fitness, Gene Conversion, Generations, Genetic, Genetic Recombination, Genetic Variation, Genome, genome sequencing, genome-wide, Genomic Instability, Genomics, Goals, Health, Individual, Infertility, Laboratories, Lead, Link, Maps, Meiosis, Meiotic Recombination, Population, programs, rate of change, recombinational repair, reproductive, Research, Saccharomyces, Shapes, Spontaneous abortion, System, Temperature, Testing, Time, Variant, whole genome, Yeasts | Department of Biology, NORTH CAROLINA STATE UNIVERSITY RALEIGH, Raleigh, NC 27695, United States |
| 1R35GM142879-01 | Yu, Kun-Hsing | Robust, Generalizable, and Fair Machine Learning Models for Biomedicine | 2021, funded from 09/01/2021 to 06/30/2022 | Project Summary Modern machine learning approaches have attained substantial success in pattern recognition and high-dimensional data analyses. However, these algorithms heavily rely on association discovery, which cannot elucidate the mechanisms underpinning the observed correlations and suffers from limited generalizability. To address this challenge, the Yu Lab focuses on the development of robust and generalizable machine learning approaches to integrate various types of biomedical data, including multi-omics, pathology, and phenotypic information. The goal of the next five years is to develop novel computational methods that connect machine learning algorithms with causal inference methodologies to better understand the molecular mechanisms underpinning disease pathology and enable fair and robust predictions of drug response and toxicity. The overall vision of the proposed research program is to establish generalizable data-driven methods to transform biomedical data into robust prediction and mechanistic models. The proposed approach will systematically connect diverse biomedical signals to extract previously unknown knowledge on the molecular mechanisms and derive reliable prediction models for the effects of medications. The proposed approaches are innovative because they depart from the status quo by incorporating advanced causal inference techniques with data-driven algorithms to enhance mechanistic and predictive modeling. This research program is significant because it is expected to improve our understanding of disease pathology and provide a fair and generalizable informatics framework for drug response and adverse effects prediction in diverse populations. The proposed research activities will open new research horizons by establishing a new machine learning platform for generating reliable predictions, which will vertically advance molecular biology, pharmacology, and computational research in biomedicine. | National Institute Of General Medical Sciences | R35 | Address, advanced disease, Adverse effects, Algorithms, analytical method, Biological, Computing Methodologies, Data, Data Analyses, Development, Disease, drug response prediction, Ensure, Goals, improved, Informatics, innovation, Knowledge, Machine Learning, machine learning algorithm, Methodology, Methods, Mission, Modeling, Modernization, Molecular, Molecular Biology, molecular modeling, multidimensional data, multiple omics, National Institute of General Medical Sciences, novel, Pathologic, Pathology, Pattern Recognition, Pharmaceutical Preparations, Pharmacology, Phenotype, Population Heterogeneity, predictive modeling, programs, Public Health, Research, Research Activity, response, Signal Transduction, success, Techniques, Toxic effect, Vision | HARVARD MEDICAL SCHOOL, Boston, MA 02115, United States |
| 1R35GM142892-01 | Murray, Dylan Thomas | Low-complexity domain protein molecular structure, conformational dynamics, and inter-protein interactions in human health and disease | 2021, funded from 09/15/2021 to 06/30/2022 | Project Summary/Abstract The dynamic assembly of biomolecules within a living cell is vital for the spatial and temporal organization of biological function. In forming RNA granule membraneless organelles and intermediate filaments in the cell cytoskeleton, cells leverage the self-assembly properties of protein sequences with reduced amino acid diversity. These low complexity protein domains have only recently come to light as essential players in these processes. Thirty percent of the proteins coded by the human genome contain a domain of this type, highlighting the central importance of these sequences for life. In humans, pathogenic genetic mutations and altered expression levels, in addition to functional post-translational modifications and protein-protein interactions, modulate the assembly processes of these proteins. Linked by the common involvement of low complexity domain proteins, this proposal outlines two lines of research focused on a fundamental mechanistic understanding of how the proteins that compose RNA granules and intermediate filament networks assemble to achieve the macroscopic behavior observed in living cells. A multifaceted biophysical approach employing cutting-edge nuclear magnetic resonance and cryo-electron microscopy will allow characterization of the molecular structure and conformational dynamics of these proteins in biologically relevant assemblies. These biophysical studies will be coupled with other spectroscopies, biochemical assays, and protein engineering to form more comprehensive models of how low complexity domain proteins assemble temporally and spatially. The results of these efforts will provide a mechanistic description of how these assembly processes and their associated control mechanisms are modulated by point mutations and altered protein expression levels linked to motor neuron disease, dementia, muscular dystrophy, and cancer. The in vitro work proposed here will provide detailed and testable models regarding the function of in vivo biological assemblies involved in RNA metabolism and the cell cytoskeleton. In the broader context of human health, the molecular characterizations of disease-relevant low complexity domain proteins and their interacting molecular partners will provide a base of knowledge useful for the exploration of these systems as clinical biomarkers and will also facilitate the development of antibody and small molecule therapeutics. Beyond the specific biological systems discussed in this proposal, the tools and methodologies employed here are expected to have applicability and impact on investigations of the thirty percent of the proteins in the human genome that contain a low complexity domain. | National Institute Of General Medical Sciences | R35 | Amino Acid Sequence, Amino Acids, Antibodies, base, Behavior, Biochemical, Biological, Biological Assay, Biological Process, biological systems, biophysical analysis, biophysical techniques, Cells, Characteristics, clinical biomarkers, Code, Coupled, Cryoelectron Microscopy, Cytoplasmic Granules, Cytoskeleton, Dementia, Development, Disease, DNA Sequence Alteration, Health, Human, Human Genome, improved, In Vitro, in vivo, Intermediate Filaments, Investigation, Knowledge, Life, Link, Malignant Neoplasms, Methodology, Microscopic, Modeling, Molecular, Molecular Conformation, Molecular Structure, Motor Neuron Disease, Muscular Dystrophies, Neurodegenerative Disorders, Nuclear Magnetic Resonance, Organelles, Pathogenicity, Play, Point Mutation, Post-Translational Protein Processing, Process, Property, Protein Chemistry, Protein Dynamics, Protein Engineering, protein expression, protein protein interaction, Proteins, Research, RNA, RNA metabolism, Role, self assembly, small molecule therapeutics, Spectrum Analysis, System, Tertiary Protein Structure, Time, tool, Work | Department of Chemistry, UNIVERSITY OF CALIFORNIA AT DAVIS, Davis, CA 95618, United States |
| 1R01NS122857-01 | Heimberger, Amy Beth, Li, Shulin (Contact) | Fgl2 neutralizing therapy for inducing tumor specific brain resident immune memory against CNS tumor relapse | 2021, funded from 08/01/2021 to 06/30/2022 | Our goal in this application is to test the hypothesis that neutralizing the newly identified immune-suppressive regulator fibrinogen-like protein 2 (Fgl2) in glioblastoma (GBM) following standard care chemotherapy will trigger tumor-specific resident memory T cells in the brain (bTrm cells), which allows immunological clearance of gliomas within the central nervous system and prevention of GBM recurrence. This hypothesis was raised based on our recently published papers and newly established preliminary data. In brief, we have discovered that Fgl2 is highly expressed in GBM tissues (Yan et al, JNCI, 2015) and can transform low-grade brain tumors to GBM (Latha et al, JNCI, 2018). Knockout of Fgl2 in tumor cells completely eliminates tumor progression in the brains of immune-competent mice but not in immune-deficient mice (Yan et al, Nat Commun, 2019). Our unpublished preliminary data have shown that neutralizing Fgl2 via administering T cells armed with a membrane-anchored anti-Fgl2 scFv induces bTrm cells that reject intracranial tumor cell challenge directly or after intracranial transplantation into naïve mice (see preliminary data section); the same mice are unable to reject tumors from peripheral tissue challenge. To test our central hypothesis, the following aims are proposed: Aim 1: Determine how T-aFgl2? neutralizing T-cell therapy induces bTrm cells in brains; Aim 2: Optimize the T-aFgl2?neutralizing cell therapy and develop a next-generation T-aFgl2 cell therapy for boosting safety and therapeutic efficacy. Impact: This study will yield a therapeutic candidate?an Fgl2-neutralizing cell therapy that may permanently prevent tumor recurrence?the key deadly cause of GBM patient death. Considering that Fgl2 can be detected in almost all GBMs, with most having very high levels, this candidate therapeutic will be important. This study will also further mechanistically elucidate how Fgl2-neutralizing cell therapy induces bTrm cells and how we can make additional improvements to move this therapy into the next phase. Ultimately, this novel field will transform the treatment of GBM. | National Institute Of Neurological Disorders And Stroke | R01 | Antibodies, Antibody Therapy, base, Biological, Brain, Brain Neoplasms, CAR T cell therapy, Cause of Death, CD3 Antigens, Cell Maturation, cell motility, Cell physiology, Cell Therapy, Cells, Central Nervous System Neoplasms, Cessation of life, chemotherapy, Clinical, Collaborations, CXCL1 gene, cytokine, cytokine therapy, Cytomegalovirus, Data, Death Domain, Dendritic Cells, Development, Effector Cell, Endothelial Cells, Exposure to, Fibrinogen, Future, Glioblastoma, Glioma, Goals, Health, Human, Immune, immune checkpoint blockade, immune clearance, Immunocompetent, Immunoglobulin Fragments, Immunologic Memory, Immunology, Immunosuppression, Immunotherapy, in vivo, Injections, Intracranial Neoplasms, ITGAX gene, Knock-out, Knockout Mice, Laboratories, Lipopolysaccharides, Longevity, macrophage, Mediating, Membrane, Memory, Modeling, Mus, Nature, neoplastic cell, Neuraxis, neutralizing antibody, next generation, novel, Paper, Patients, PECAM1 gene, Peptides, Peripheral, Phase, polyclonal antibody, Preparation, prevent, Prevention, programmed cell death ligand 1, Proteins, Publishing, Recurrence, Regulatory T-Lymphocyte, Relapse, Research, residence, Role, Safety, Signal Transduction, Solid Neoplasm, Source, standard care, subcutaneous, T cell therapy, T memory cell, T-Cell Activation, T-Cell Proliferation, T-Lymphocyte, Testing, therapeutic candidate, Tissues, TP53 gene, transcriptome sequencing, Translations, Transplantation, Treatment Efficacy, Treatment Failure, tumor, tumor growth, tumor progression, Veins | Department of Pediatrics, UNIVERSITY OF TX MD ANDERSON CAN CTR, Houston, TX 77030, United States |
| 1R01AR078245-01A1 | Fisher, Matthew B (Contact), Mcnulty, Amy L, Shirwaiker, Rohan | Using 3D Nonwovens Fabrication to Engineer Region-Specific Extracellular Matrix Structure and Bioactivity of the Knee Meniscus | 2021, funded from 07/01/2021 to 06/30/2022 | PROJECT SUMMARY Meniscal tears are the most commonly reported knee injuries, and approximately 1 million surgeries involving the meniscus are performed annually in the US. Tissue engineering and regenerative medicine approaches are being actively pursued as potential alternatives to overcome limitations of current clinical treatments. Yet, the translation of these approaches to clinical application has been hampered by their limited ability to efficiently and reproducibly create physiologic-sized scaffolds featuring anisotropic structural and mechanical properties on the order of native meniscus and zone-specific biological cues provided by the ECM. The overall goals of this proposal are to 1) develop a scaffold that recapitulates the complex structural and mechanical characteristics of the meniscus at multiple scales and incorporates zone-specific ECM cues and 2) assess the long-term function of such scaffolds and their ability to prevent joint degeneration in-vivo. We will use a new high-throughput hybrid approach of 3D Melt Blowing (3DMB) in conjunction with Solution Blowing (SB) that synergistically integrates attributes of traditional nonwovens techniques and 3D printing to create a scaffold featuring macro-geometry, fibrous microarchitecture, and zonal biological cues (meniscus-derived ECM (mECM)) to match the native meniscus. We hypothesize that both biomechanics and mECM cues need to be similar to the meniscus to achieve superior in-vivo outcomes, primarily, reduced cartilage degeneration. Aim 1 is to determine how primary 3DMB and SB process variables influence the structural architecture and biomechanical properties of anatomically-sized meniscus scaffolds made of selected biopolymers and mECM. Aim 2 is to determine whether the incorporation of zone-specific mECM improves infiltration and tissue formation by cells as well as integration with the surrounding meniscus tissue. Aim 3 is to determine whether cartilage degeneration following partial meniscectomy is reduced through the addition of an appropriate mECM formulation within scaffolds with meniscus-matched mechanics. On completion, this project will provide fundamental knowledge about the micro- and macro-level process-structure-function relationships in meniscus-relevant bioactive scaffolds fabricated using our new nonwovens approach, and will serve as a base technology of great significance allowing advances in the treatment of orthopaedic fibrous soft tissue injuries. | National Institute Of Arthritis And Musculoskeletal And Skin Diseases | R01 | 3-Dimensional, 3D Print, Anatomy, Architecture, base, Behavior, Biological, Biomechanics, Biopolymers, Caliber, cartilage degradation, Cell Culture Techniques, Cell Differentiation process, Cell Survival, Cells, Characteristics, clinical application, Clinical Treatment, Collagen, Complex, Control Groups, Cues, Data, design, Electrospinning, Engineering, Extracellular Matrix, Family suidae, Fiber, Formulation, Geometry, Goals, Hybrids, Implant, improved, In Vitro, in vivo, Infiltration, Injury, Intervertebral disc structure, joint destruction, Joints, Knee, Knee Injuries, Knowledge, Ligaments, mechanical properties, Mechanics, melting, meniscal tear, meniscus injury, Meniscus structure of joint, Modeling, Morphology, novel, Operative Surgical Procedures, Orthopedics, Outcome, Patient-Focused Outcomes, Patients, Physiological, Polyesters, Polymers, Polyurethanes, Porosity, prevent, Process, Production, Property, Proteomics, Public Health, Regenerative Medicine, repaired, Reporting, Reproducibility, Research, scaffold, Shapes, socioeconomics, Soft Tissue Injuries, Stifle joint, Structure, Structure-Activity Relationship, Surgical sutures, Synovial Cell, System, Techniques, Technology, Tendon structure, Testing, three dimensional structure, Tissue Engineering, Tissues, Translations, Work | Department of Engineering (All Types), NORTH CAROLINA STATE UNIVERSITY RALEIGH, Raleigh, NC 27695, United States |
| 1R35GM142902-01 | Medina, Scott Hammond | Understanding and controlling the cellular fate of fluorine-modified biologics | 2021, funded from 07/01/2021 to 06/30/2022 | PROJECT SUMMARY Organofluorine compounds possess attractive chemical, pharmacological and biological properties that have allowed them to make paradigm shifts in the design of biopharmaceuticals and biologic materials. The introduction of fluorine atoms into amino acids and nucleic acids opens a vast new chemical landscape with which to alter the folding, stability, oligomerization propensity and bioactivity of peptides, proteins and DNA. However, although shown to impart favorable properties, the impact of adding fluorine into biologic scaffolds is rarely predictable. Further, increasing evidence suggests perfluorinated compounds promiscuously adsorb to many of the fundamental building blocks of cells - including lipids, proteins and DNA - to elicit a plurality of bioeffects. One of these effects, recently discovered by the PI?s lab, is the ability of organofluorine molecules to direct protein and DNA assembly into fluorous microdomains that phase separate into fluorinated liquids without denaturing the biologic. The PI has recently exploited these emergent properties to enable ultrasound-guidance of fluorinated proteins in three-dimensional tissues. Building upon these preliminary findings, the proposed research program will mechanistically explore how organofluorine compounds influence the structure and function of adsorbed proteins and DNA and use these insights to guide the design of new supramolecular assembled biomaterials. Our overarching hypothesis is that organofluorine compounds non-covalently adsorb to proteins and DNA to direct their separation into fluorine-rich phases, which in turn alters their oligomeric assembly, cellular fate and bioactivity. To test this assertion, we will expand our perfluorinated compound (PFC) library to include a diversity of molecules with basic/acidic functionalities and heterocyclic moieties. We will use this library to establish structure-activity relationships governing the ability of PFCs to adsorb proteins, and investigate how PFC complexation alters protein cellular uptake, intracellular trafficking and bioactivity. In parallel, we will use this library to study the molecular mechanisms mediating PFC-DNA interactions and examine how PFC complexation alters DNA stability and metabolic homeostasis in exposed cells. Together, these studies will establish a comprehensive mechanistic understanding of how PFCs interact with proteins and DNA and will allow us to rationally design fluorous biotechnologies that exploit the unusual assembly phenomenon and phase- separation properties that emerge. As an example, we will create ultrasound-sensitive fluorine nanoemulsions loaded with PFC-modified ribonucleoproteins (RNPs) to enable imaging-guided gene editing in kidney tissue. Success of this research will advance the use of PFCs as a new molecular motif to control protein and DNA assembly, and the methods developed applied to discover new reagents for intracellular transduction of fluorinated biomacromolecules. Ultimately, advancing knowledge on how organofluorine compounds interact with proteins and DNA, and its effects on cells, will guide the rational design of new PFC enabled technologies with desirable functional properties for drug discovery and nanomedicine applications. | National Institute Of General Medical Sciences | R35 | 3-Dimensional, Amino Acids, Biocompatible Materials, Biological, Biological Products, biomacromolecule, Biotechnology, Cells, Chemicals, Complex, design, DNA, DNA Maintenance, drug discovery, Fluorine, Genes, Homeostasis, image guided, insight, Kidney, Knowledge, Libraries, Lipids, Liquid substance, Mediating, Metabolic, Methods, Molecular, nanoemulsion, nanomedicine, novel therapeutics, Nucleic Acids, Peptides, Pharmacology, Phase, physical property, Play, programs, Property, Proteins, Reagent, Research, Ribonucleoproteins, scaffold, Structure, Structure-Activity Relationship, success, Technology, Testing, Tissues, trafficking, Ultrasonography, uptake | Department of Biomedical Engineering, PENNSYLVANIA STATE UNIVERSITY-UNIV PARK, University Park, PA 16802, United States |
| 1R35GM142938-01 | Jackrel, Sara Lindsay | Identifying the Rules Governing Host-Microbiome Composition and Function | 2021, funded from 08/01/2021 to 05/31/2022 | Project Summary/Abstract All eukaryotes harbor host-associated microbiomes. Determining what regulates host-microbiome function has the potential to revolutionize our approaches towards maintenance of host health. Host genetics and the environment are two key factors that contribute towards host-microbiome composition and function. We aim to advance our understanding of the relative roles of these two factors in regulating assembly of microbial communities, short-term changes in these communities through ecological succession, and long-term changes through evolutionary processes. Further, microbiomes are complex biological networks. Understanding the underlying structure of ecological interactions within these networks can improve predictions for when and how microbiomes might confer beneficial versus deleterious functions associated with disease. Our lab aims to advance fundamental understanding of host-microbiomes by leveraging the microbiomes of microbes. Specifically we employ single-celled eukaryotic phytoplankton as a highly-tractable experimental system. To further these goals we will focus on the following three themes over the next five years. (1) We will couple the unparalleled diversity of phytoplankton with bacterial ?omics approaches to test how microbiomes assemble in response to host genetics. By assessing bacterial gene expression responses to host genetics, in tandem with fluctuating environmental conditions, this work will lend insights in to the host genetic x environmental forces that drive microbiome assembly of eukaryotic microbiomes. (2) We will evaluate mechanisms of microbiome change for maintenance of host homeostasis in fluctuating environments, including ecological shifts in bacterial taxonomic composition, shifts in bacterial gene expression, and bacterial strain evolution. It is important to understand the relative roles of these mechanisms because each occurs over different timescales and their effects can have varying degrees of permanence on their host. (3) We will leverage classical community ecology theory in biological networks with recent advances in flow cytometry bacterial fingerprinting to characterize traits of transient versus stable microbiome networks. We will quantify bacteria-bacteria interaction strengths within naturally assembled and engineered microbiomes to understand how network structure contributes to transitions between host health and disease states. Additionally, our research program will elucidate the implications of declining microbial diversity on eukaryotic host health. We will study host- microbiome co-evolutionary mismatches, such as those caused by humans consuming processed diets and living in human-built environments that differ from those of our evolutionary history. Ultimately, our work will leverage a highly tractable experimental system to advance our understanding of the microbiomes that modulate human health. | National Institute Of General Medical Sciences | R35 | Bacteria, Bacterial Genes, base, Biological, built environment, Communities, Complex, Consumption, Diet, Disease, Ecology, Engineering, Environment, Eukaryota, Eukaryotic Cell, Evolution, Fingerprint, Flow Cytometry, Gene Expression, Genetic, Goals, Health, Homeostasis, host microbiome, Human, improved, insight, Maintenance, Microbe, microbial, microbial community, microbiome, microbiome composition, Phytoplankton, Process, programs, Recording of previous events, Research, response, Role, Structure, System, Taxonomy, Testing, theories, Therapeutic, trait, Work | Department of Biology, UNIVERSITY OF CALIFORNIA, SAN DIEGO, La Jolla, CA 92093, United States |
| 1R01HS028455-01 | Elston Lafata, Jennifer M | Development of a Shared Decision Making Support (SDM-S) Measure for Use with Team-based Care | 2021, funded from 09/01/2021 to 08/31/2022 | Abstract As health care has become more complex, shared decision making (SDM) becomes increasingly important and is now required by the Centers for Medicare and Medicaid Services (CMS) prior to reimbursement for some services. Despite such requirements, we do not yet have a way to monitor the quality of medical decision-making in today?s practice environment. This void limits the impact of policies requiring the use of SDM as well as the ability to either foster SDM or understand its effects in practice. In this application, we build on our team?s clinical and medical decision-making expertise to develop valid and psychometrically sound, patient-reported SDM-support (SDM-S) measures that consider four distinct, decision-making phases (i.e., choice awareness, consideration of alternatives/preferences, choice-making, and choice implementation), and the language used by patients to describe how decision making unfolds in practice. In so doing, we seek to advance the SDM measurement field from a researcher, single scale orientation to a multiphase/multi subscale orientation that explicitly considers the decision-making support patients describe receiving from their physician and different care team members across each of the decision-making phases from decision awareness to choice implementation. Such an orientation is needed as providers and others explore new and innovative ways to implement and monitor SDM in practice. We use mixed-method and user-centered design approaches to develop the measures and test their performance across four preference-sensitive cancer care contexts: lung cancer screening, colorectal cancer screening, rectal cancer treatment, and prostate cancer treatment. We evaluate scale performance and acceptability among the diverse populations served in real-world primary and oncology care settings. Our specific aims are to: Aim 1. Develop psychometrically sound clinician-specific and overall team SDM-S subscales for each decision phase; Aim 2. Evaluate and compare the predictive validity of the clinician-specific vs. overall team SDM-S subscales across and within decision phases; and Aim 3. Evaluate patient acceptability of SDM-S scales in real-world primary and oncology care settings. Results will enable monitoring the phase-specific quality of SDM-S provided within today?s team-based care models across diverse cancer screening/treatment decisions and patient subgroups. As such, study findings will provide actionable targets for those wanting to monitor and improve patient-centered care and important measurement tools for those studying the impact of SDM on patient and other outcomes. 1 | Agency For Healthcare Research And Quality | R01 | UNIV OF NORTH CAROLINA CHAPEL HILL, Chapel Hill, NC 27599, United States | |
| 3B09SM010011-09S2 | Walliby, Kerio | Block Grants for Community Mental Health Services | 2009, funded from 10/01/2008 to 09/30/2010 | Center For Mental Health Services | B09 | FEDERATED STATES MICRONESIA, Pohnpei, , Fed Micronesia | ||
| 1R01CA262290-01 | Janda, Kim | High-Throughput Screen for the Oncoprotein MYC | 2021, funded from 07/01/2021 to 06/30/2022 | ABSTRACT MYC is a key transcriptional regulator involved in cellular proliferation and has established roles in transcriptional elongation and initiation, microRNA regulation, apoptosis, and pluripotency. More importantly, MYC has been directly implicated in over 50% of human cancers and is recognized as a general hallmark of cancer initiation and maintenance. Despite this prevalence, there are few functional chemical probes for MYC and no therapeutics that target it. We have discovered a compound, KJ-Pyr-9, that binds to MYC with high potency and specificity, downregulates the transcriptional activities of MYC and, most importantly, is the first MYC ligand that shows efficacy in vivo. However, while SAR efforts were able to improve the pharmacokinetic and pharmacodynamic properties of the scaffold, it remains insufficient for therapeutic use. This endeavor did yield several valuable probes, one of which, RSH470, exhibits an increase in fluorescence in the presence of MYC. HDX-MS experiment revealed that RSH470 binds a novel site in the critical bHLH-LZ motif of MYC. Excitingly, modeling and single amino acids mutations of the site have validated this finding and provided a structural explanation of the inhibitor mechanism. Utilizing RSH470, we have developed the first fluorescence-based HTS screening competition assay that specifically identifies MYC inhibitors and does not require protein modification, DNA binding, or the complimentary dimer partner MAX. Furthermore, it is simple, inexpensive, and free of proprietary restrictions that limit available HTS assays for MYC. The effectiveness of this assay has been validated by established orthogonal methods (BLI, Bio-FET, SPR) and cellular oncogenic transformation experiments. Furthermore, structurally distinct compounds, with specific cellular activity, have been discovered by pilot screens performed on both Scripps Research campuses. In this proposal, we present a strategy to screen of the entire >665,000 Scripps Drug Discovery Library (SDDL) to identify novel MYC inhibitor scaffolds. A secondary HTS with and without MYC will determine whether hit activity is MYC dependent. Hits selected by a medicinal chemist will then be validated by bio-layer interferometry (BLI), surface plasmon resonance (SPR), and field-effect transistor analysis (Bio- FET). Cellular potency and MYC specificity will be established through oncogenic transformation assays with orthogonal oncogenes as well as with inhibitor resistant MYC mutants cell lines. The pharmacokinetics properties of leads compounds will be assessed in vitro before their final evaluation in an established xenograft model. This research program will produce a set of precisely characterized chemical leads with a strong correlation between in vitro and in vivo efficacy. Not only will these compounds be beneficial in the study MYC functions, but they will may lead to a therapeutic strategy for MYC driven cancers. | National Cancer Institute | R01 | acute toxicity, Affect, Affinity, Amino Acids, Animal Model, Apoptosis, Attenuated, base, Binding, Binding Proteins, Binding Sites, Biological Assay, Biology, Breast Cancer Model, California, cancer initiation, Cell division, cell growth, Cell Line, Cell model, Cell Proliferation, Cells, Cellular Assay, Chemicals, Chickens, ChIP-seq, Competitive Binding, Complex, Development, dimer, Dimerization, Disease, DNA Binding, Dose, drug discovery, Drug Kinetics, E-Box Elements, Effectiveness, efficacy evaluation, Embryo, Ensure, Evaluation, Exhibits, experimental study, Fibroblasts, Florida, Fluorescence, Fluorescent Probes, Follow-Up Studies, Gatekeeping, Genetic Transcription, high throughput screening, Histologic, Human, Human Cell Line, improved, In Vitro, in vivo, inhibitor/antagonist, Interferometry, Label, Lead, Libraries, Ligands, Light, Maintenance, Malignant Neoplasms, Methods, MicroRNAs, Modeling, mutant, Mutation, MYC gene, Nature, non-Native, novel, Oncogenes, Oncogenic, Oncoproteins, Pharmaceutical Chemistry, Pharmaceutical Preparations, pharmacokinetics and pharmacodynamics, Phenotype, Plasma, Plasma Proteins, pluripotency, Post-Translational Protein Processing, Prevalence, Process, programs, Property, Proteins, Regulation, Research, Resistance, Role, Running, scaffold, screening, Series, Site, Specificity, Structure, Surface Plasmon Resonance, Testing, Therapeutic, therapeutic target, Therapeutic Uses, Tissues, Toxic effect, Transcription Elongation, transcription factor, Transcription Initiation, Transistors, tumor, tumor growth, United States National Institutes of Health, Validation, Xenograft Model | SCRIPPS RESEARCH INSTITUTE, La Jolla, CA 92037, United States |
| 1R01CA262287-01 | Savona, Michael R (Contact), Shah, Jatin J., Vanderlaag, Kathyrn | Development of a Phenotype-based Predictive Analytic for Acute Myeloid Leukemia | 2021, funded from 09/15/2021 to 08/31/2022 | Project Summary The 5-year overall survival from acute myeloid leukemia (AML) is less than 30%. While some patients are cured with initial induction therapy, most patients relapse, and the expected outcomes in patients with relapsed and refractory (R/R) AML are dismal. For this reason, developing methods to identify therapies likely to benefit R/R AML patients is a top priority. This proposal aims to address critical unmet needs with a unique Academic- Industry Partnership (AIP) between investigators at Vanderbilt University Medical Center, Karyopharm Therapeutics, and Notable Labs. The BCL2 inhibitor, venetoclax (VEN), is transforming clinical practice for AML, but activity in R/R AML is less pronounced, and resistance occurs in most patients. AIP investigators currenty lead a multi-site investigator-sponsored study, testing VEN in combination with the selective inhibitor of nuclear export (SINE) selinexor (SEL) in a Phase I trial for R/R AML (NCT03955783). This SEL/VEN trial grew from the discovery that SEL synergizes with VEN and overcomes resistance mechanisms in some VEN-insensitive patient samples. Given this, our AIP team has worked together to develop a precision medicine functional platform for this novel combination in R/R AML. Notable Labs utilizes an automated high-throughput, immunophenotype-based flow cytometry method to provide real time drug sensitivity data on multiple, specific cell populations simultaneously within a given patient sample. Building from the only annotated cohort of patient samples treated with SEL/VEN in the world, we propose to develop a precision medicine functional assay to identify R/R AML patients most likely to benefit from SINE/VEN combination therapy. We will build, refine and optimize the functional platform for SEL/VEN with samples from our current Phase I study and train the platform on samples from the Phase 2 SEL/VEN clinical trial proposed by the AIP. Aim 1 will focus on determining assay parameters specifically for SEL/VEN in R/R AML. Aim 2 will train the model with the phase II clinical trial of SEL/VEN in R/R AML, and Aim 3 will contextualize the predictive analytic model on heterogenous genotypes found in R/R AML. At the conclusion of this study, the functional medicine platform will be a companion diagnostic ready for external validation which we will lead in a phase III efficacy trial of SEL/VEN in R/ R AML, and serve as proof-of-principle for development of similar therapy-specifc precision medicine tools. | National Cancer Institute | R01 | Academic Medical Centers, Acute Myelocytic Leukemia, acute myeloid leukemia cell, Address, alternative treatment, analytical tool, antitumor effect, base, BCL2 gene, Biological Assay, Caring, Cell Line, Cell Nucleus, Cells, Clinical, Clinical Management, clinical practice, Clinical Trials, cohort, Combined Modality Therapy, companion diagnostics, Cytoplasm, Data, Data Set, Dependence, Development, Disease, Disease-Free Survival, Dose, drug sensitivity, effective therapy, Effectiveness, efficacy trial, Evaluation, Excision, Exhibits, exportin 1 protein, Exportins, Family, Flow Cytometry, FLT3 gene, Gene Mutation, Genetic Markers, genetic resistance, Genomics, Genotype, high risk, Immunophenotyping, Industry, industry partner, inhibitor/antagonist, Investigation, Laboratories, Lead, leukemia, leukemia initiating cell, Leukemic Cell, Link, MCL1 gene, Measurement, Medicine, Methods, Minority, Modeling, monocyte, Mutate, Mutation, Neoadjuvant Therapy, new combination therapies, novel, novel therapeutics, Nuclear, Nuclear Export, older patient, Outcome, Patient Education, Patient-Focused Outcomes, Patients, Pattern, Phase, phase 1 study, phase 2 study, phase I trial, Phase II Clinical Trials, phase II trial, Phenotype, Phosphotransferases, Play, Population, precision medicine, preclinical efficacy, preclinical study, predicting response, Predictive Analytics, pressure, protein transport, Proteins, RAS Family Gene, Refractory, Regimen, Relapse, relapse patients, Reproducibility, Research, Research Personnel, Resistance, resistance mechanism, responders and non-responders, response, Role, Safety, Sampling, Selection for Treatments, Sensitivity and Specificity, single cell technology, Site, Specificity, standard of care, targeted sequencing, targeted treatment, Testing, Therapeutic, Time, tool, TP53 gene, Training, translational study, Translations, Tumor Suppressor Proteins, Validation, Work | VANDERBILT UNIVERSITY MEDICAL CENTER, Nashville, TN 37232, United States |
| 1U19AG073172-01 | Andersen, Stacy, Bookheimer, Susan Y, Perls, Thomas T (Contact) | Resilience/Resistance to Alzheimer's Disease in Centenarians and Offspring (RADCO) | 2021, funded from 09/30/2021 to 05/31/2022 | Overall Component Summary Centenarians delay age-related diseases and disabilities into their mid-nineties. Some remain cognitively intact despite extreme exposure to the strongest risk factor for cognitive impairment and AD, aging. The overall hypothesis of this study, titled ?Resilience/Resistance to AD in Centenarians and Offspring? (RADCO), is: centenarian cognitive superagers and some of their offspring have protective factors that confer such resilience or in some cases, even resistance against cognitive decline and dementia. RADCO assembles an unprecedentedly large sample of prospectively studied centenarian cognitive superagers (n=495, essentially, centenarians with cognitive function that falls within the norms of septuagenarians) along with offspring (n=600) and offspring spouses (n=120), who, via RADCO cores, undergo careful, comprehensive and cutting edge neuropsychological, biomarker, neuroimaging and neuropathological phenotyping. These data are used by two projects with the overall scientific objective of gauging cognitive resilience in this sample, understanding the underlying protective biology and translating that into therapeutic targets. The Cognitive Resilience and Resistance Phenotypes Project (Project 1) gauges resilience by neuroimaging, plasma AD biomarkers risk and neuropathology and therefore generates a range of resilience endophenotypes. The Protective Factors and Mechanisms Project (Project 2) is the translation arm of RADCO; it discovers genes, candidate biological pathways and sets of mi-RNA regulators associated with the resilience endophenotypes characterized in Project 1. In-vitro models of AD incorporate cortical neurons, microglial cells and astrocytes created from centenarian cognitive superager induced pluripotent stem cell (iPSC) lines are used to test the candidate pathways for how they cause resilience against AD. | National Institute On Aging | U19 | 3-Dimensional, age related, Aging, Alzheimer associated neurodegeneration, Alzheimer's Disease, Alzheimer's disease model, Alzheimer's disease pathology, Area, arm, Astrocytes, Biological, Biological Assay, Biological Markers, Biology, Blood, Brain, Brain Pathology, Cell Line, Cellular Assay, Centenarian, circulating biomarkers, Cognitive, cognitive function, cognitive testing, Data, Dementia, Development, disability, Disease, drug candidate, Drug Combinations, Drug usage, endophenotype, exome, Exposure to, falls, Functional Magnetic Resonance Imaging, gene discovery, Genes, genetic variant, Human, Impaired cognition, in vitro Model, indexing, induced pluripotent stem cell, Lead, Life Expectancy, Measures, Microglia, microRNA biomarkers, MicroRNAs, Modeling, Molecular, neuroimaging, neuroinflammation, Neurons, neuropathology, Neuropsychology, offspring, Organoids, Pathway interactions, Pharmaceutical Preparations, Phenotype, Plasma, Prospective Studies, protective factors, relating to nervous system, resilience, Resistance, Risk, Risk Factors, RNA, RNA Sequences, Sampling, Septuagenarian, Serum, sex, Spouses, Structure, Testing, Therapeutic, therapeutic target, Tissues, Translating, translational study, Translations, Work | Department of Internal Medicine/Medicine, BOSTON UNIVERSITY MEDICAL CAMPUS, Boston, MA 02118, United States |
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