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NIH RePORTER provides a list of funded grants across NIH institutes.
(last updated: Mar 25, 2022)
Funding Grants| Project Number | PI Names | Project Title | Grant Code | Funding Year | Funding Institute | Funding Institute Abbreviation | |||
|---|---|---|---|---|---|---|---|---|---|
| 1R21CA254968-01 | Manor, Danny | Understanding and Targeting Tiam1 in Cancer | R21 | 2021 | National Cancer Institute | NCI | Project Summary: Understanding the detailed mechanisms that underlie proliferative signal transduction pathways is of critical importance for developing strategies for diagnosis and treatment of human cancer. Because most proliferative pathways are critical for the functioning of all normal cells, the development of cancer-cell-selective interventions without off-target effects is tremendously important yet highly challenging. The research proposed in this grant application focuses on unique ?players? in proliferative signaling, the guanine nucleotide exchange factors (GEFs) from the Dbl (diffuse B cell lymphoma) family. GEFs control proliferative signaling by stimulating nucleotide exchange on the small GTPases, Rho, Rac, and Cdc42. In doing so, GEFs regulate numerous cellular activities such as gene expression, cytoskeletal rearrangements, protein synthesis, and metabolism. Gain-of-function mutations in GEFs are associated with multiple human cancers, and GEFs from the Dbl family constitute one of the largest families of proto-oncogenes. Although different Dbl-family GEFs share similar mechanisms of action, their expression is extremely tissue- and cell-specific, and their respective mutated forms are associated with distinct and different cancers. Thus, intervention with GEF signaling may be extremely useful in multiple, seemingly unrelated malignant diseases. The proposed work relies on our recent discovery of a novel tyrosine phosphorylation sequence motif (TEXXYVXXL) that regulates the activity of some Dbl-like GEFs implicated in human cancers. We hypothesize that selective interreference with this phosphorylation comprises a unique, novel and effective selective intervention approach in relevant cancers. This proof-of-principle proposal focuses on Tiam1, a GEF whose dysregulation drives colorectal tumorigenesis and metastasis. We propose to decipher the molecular mechanisms and functional outcomes of TEXXYVXXL phosphorylation in Tiam1, and to test novel reagents that target Tiam1?s tyrosine phosphorylation as selective intervention tools. In Specific Aim 1 we will decipher the role of TEXXYVXXL phosphorylation in regulating Tiam1?s key activities, i.e. GTPase activation, cell invasion and proliferation in vitro, and tumorigenesis and metastasis in vivo. In Specific Aim 2, we will evaluate the utility of novel reagents that target Tiam1?s TEXXYVXXL phosphorylation site for intervention in a mouse model of colon cancer. These proof-of-concept experiments in cells and animals will open the door for future development and translational work in GEF-associated malignancies. | Affect, Amino Acid Sequence, Animal Model, Animals, Applications Grants, Automobile Driving, B-Cell Lymphomas, base, Biological, Biological Process, cancer cell, cancer therapy, Cell Cycle Progression, cell motility, Cell Proliferation, cell transformation, Cells, Colon, colon cancer treatment, Colon Carcinoma, colon tumorigenesis, Colorectal Cancer, Consensus Sequence, Conserved Sequence, Critical Pathways, Cytoskeleton, Data, Development, Diagnosis, Diffuse, Disease, Event, experimental study, Family, functional outcomes, Future, gain of function mutation, Gene Expression, Genes, Guanine Nucleotide Exchange Factors, Guanosine Triphosphate Phosphohydrolases, Homologous Gene, Human, improved, in silico, In Vitro, in vivo, innovation, Intervention, Malignant - descriptor, Malignant Neoplasms, Measures, Mediating, Metabolism, migration, Modification, Molecular, Monomeric GTP-Binding Proteins, mouse model, Mutate, Mutation, Neoplasm Metastasis, new therapeutic target, Normal Cell, novel, Nucleotides, Oncogenic, Outcome, Pathway interactions, Pharmaceutical Chemistry, Phosphorylation, Phosphorylation Site, Physiological, Post-Translational Protein Processing, promoter, Protein Biosynthesis, protein function, protein metabolism, Proto-Oncogenes, Reagent, Research, rho, rho GTP-Binding Proteins, Role, Signal Pathway, Signal Transduction, Signal Transduction Pathway, Site-Directed Mutagenesis, small molecule inhibitor, Specificity, Structure, Structure-Activity Relationship, Surface, Testing, Tissues, tool, tumor, tumorigenesis, Tyrosine, Tyrosine Phosphorylation, Work, Xenograft procedure | Department of Nutrition, CASE WESTERN RESERVE UNIVERSITY, Cleveland, OH 44106, United States |
| 1R01MH124789-01 | Werge, Thomas | Road Map to Precision Psychiatry: Comprehensive Investigation of Chromosomal Anomalies (PsychMap) | R01 | 2021 | National Institute Of Mental Health | NIMH | Summary Background: While the past decade has provided insight into the genetic architecture of complex traits and disorders, the identified genetic associations are fraught with complex patterns of heterogeneity and clinical pleiotropy, especially in psychiatry. Also, little is yet known about pathogenic and societal impact of disease- predisposing genomic variants at the level of an individual or an entire population, since many of them confer very modest increases in disease risk. Recurrent copy number variants (CNVs) and sex chromosome aneuploidies (SCAs) are well suited to break the impasse and pilot efforts in precision psychiatry with their reasonable prevalence and sizable disease risk. Aims: We will first provide truly unbiased estimates of prevalence, as well as age-dependent hazard and disease penetrance, of recurrent CNVs and SCA; second, determine the global burden of disease (GBD) of these genomic alterations; and third, transform these findings into clinical recommendations for actionable genetic testing and planning of healthcare provision. Additionally, we will determine the degree to which pathologic profiles of CNV/SCA differ between clinically ascertained carriers (who form the basis of most hitherto research of pathogenicity of CNVs/SCAs) and carriers whose carrier status is unknown by the healthcare system. Methods: We will (a) leverage a genotyped case-cohort psychiatric sample truly representative of the Danish population (n[psych]=90.000; n[cohort]=50,000) to determine carrier status of recurrent CNVs at 54 genomic loci as well as for SCA, (b) cross-reference detailed clinical, demographic and socio-economic person-level data from public, nationwide registries, in order to (c) estimate for each of the chromosomal anomalies (i) the Population prevalence, Penetrance and Hazards for individual psychiatric and somatic diagnoses, (ii) the corresponding life-time disease trajectories and (iii) the disease burden, using (d) (i) Cox Proportional Hazards models with inverse sampling probability weights, (ii) Sequence Analysis and (iii) standard health economic measures, incl. DALY and direct and indirect healthcare costs. Some of these methods have been developed specifically over the last years in cooperation between the research groups of the Danish and U.S. based applicants. To determine the impact of ascertainment bias on perceived disease rates of carriers, we?ll cross- reference the Danish population sample carriers with records from the Danish cytogenetic register and compare clinically known vs. unknown carriers, and also compare overall disease rate in the Danish population sample carriers with a large clinical sample of SCA carriers from the U.S. | Address, Age, age related, Aneuploidy, Attention, base, biobank, burden of illness, care outcomes, care systems, carrier status, Clinical, clinical phenotype, cohort, Complex, Copy Number Polymorphism, cost, Cox Proportional Hazards Models, Cytogenetics, Data, data registry, Databases, Denmark, Derivation procedure, Diagnosis, disability-adjusted life years, Disease, disorder risk, DNA Sequence Alteration, Economic Burden, Economics, Education, Employment, Epilepsy, Fertility, Frequencies, Gender, General Population, Genes, genetic architecture, genetic association, Genetic Models, Genetic Risk, genetic testing, genetic variant, genomic locus, Genotype, Gold, Guidelines, hazard, Health, Health Care Costs, health economics, health service use, Healthcare, Healthcare Systems, Heterogeneity, improved, Incidence, Individual, insight, interest, Investigation, Life, Link, Longevity, Maps, Measures, Medical, Mental disorders, Methods, mortality, Nature, neuropsychiatry, novel, Occupational, Outcome, Parental Ages, Parents, Pathogenicity, Pathologic, Patient Care, Patients, Pattern, Penetrance, Personal Satisfaction, personalized medicine, Persons, Phenotype, pleiotropism, Policy Maker, Population, population based, precision medicine, Prevalence, Probability Samples, Psyche structure, Psychiatry, Recommendation, Records, Recurrence, Registries, Research, Research Design, Risk, Risk Estimate, risk variant, Sampling, Schools, Secure, Sequence Analysis, Services, sex chromosome aneuploidy, Social Work, societal costs, sociodemographics, socioeconomics, Specificity, Therapeutic Intervention, Time, tool, trait, Translations, Universities, Weight, whole genome | REGION HOVEDSTADEN, Hilleroed, 3400, Denmark |
| 4R42EY029625-02 | Handa, James T, Kocab, Andrew Joseph (Contact) | Therapeutic inhibition of Fas-mediated retinal cell death and inflammation in dry AMD | R42 | 2020 | National Eye Institute | NEI | PROJECT SUMMARY / ABSTRACT Age-related macular degeneration (AMD) is the leading, and due to the aging baby boomers, a growing cause of irreversible vision loss in the United States, and is strongly associated with exposure to cigarette smoke (CS) and high fat diets (HFD). While effective treatment is available for neovascular AMD, the AREDS II antioxidant vitamins are the only proven treatment for intermediate dry AMD. Unfortunately, AREDSII is not effective for early or late dry disease, and in intermediate AMD, it merely slows the progression to advanced disease. Treatments that target dry AMD will have a huge impact on the afflicted individual and save billions of health care dollars per year. Impairment of the oxidative stress response, autophagy, mitochondrial function, and the unfolded protein response, as well as dysregulated innate immunity have been implicated in AMD, and thus, have been investigated as treatment targets. Ultimately, these abnormalities cause death of retinal pigment epithelial (RPE) cells and photoreceptors (PR), leading to permanent vision loss. Fas-mediated cell death is the major mechanism of outer retinal cell loss in many retinal diseases including AMD. With no therapy to prevent Fas-mediated outer retinal cell death in AMD, a logical treatment strategy is to prevent Fas- mediated signaling, irrespective of the upstream impairment. ONL Therapeutics, an ophthalmic biotechnology company developing innovative therapies that prevent retinal cell death to improve visual outcomes for patients, has demonstrated the effectiveness of Fas inhibition in preventing retinal cell death in an acute model of AMD. Additionally, a gene therapy that inhibits Fas signaling has been developed and tested in acute and chronic models of glaucoma, wherein the vector provided significant inner retinal neuroprotection. Due to the role of Fas in AMD and the effect of Fas inhibition in protecting the retina following ocular stress, this proposal will examine the effect of the Fas inhibitors in acute and chronic models of atrophic AMD. Phase I of this Fast- track STTR proposal will i) determine the feasibility of using Fas inhibition to protect against acute CS-induced retinal damage, and ii) demonstrate that the duration of inhibition is clinically meaningful. Phase II will test the ocular safety and effectiveness of repeated intravitreal injections of our peptide Fas inhibitor. In addition, we will test the effectiveness of repeated intravitreal injections of the peptide Fas inhibitor as well as a single intravitreal injection of a Fas inhibitor vector in a novel, peer-reviewed chronic model of atrophic AMD in which apoB100 mice exposed to CS and HFD develop a geographic atrophy phenotype that closely resembles human disease. This proposal combines the expertise of ONL and the Wilmer Eye Institute to test these Fas inhibitors in models of atrophic AMD. Successful execution of the project will support the continued pre-clinical development of the Fas inhibitors for dry AMD and help attract additional investor interest in the company. | Acute, Address, advanced disease, Age related macular degeneration, Aging, Anatomy, Antioxidants, Atrophic, Autophagocytosis, baby boomer, biological adaptation to stress, Biotechnology, Blindness, Cause of Death, CD95 Antigens, Cell Death, Cell Survival, Cells, Cessation of life, Chronic, cigarette smoke, cigarette smoke-induced, Clinical, Clinical Research, Clinical Trials, commercial application, commercialization, Data, Decision Making, Development, Disease, Disease Progression, Dose, economic impact, effective therapy, Effectiveness, effectiveness testing, Exhibits, Exposure to, exposure to cigarette smoke, Exudative age-related macular degeneration, Eye, Foundations, Fundus, gene therapy, geographic atrophy, Glaucoma, Healthcare, High Fat Diet, Histologic, human disease, Impairment, improved, Individual, Inflammation, Inflammatory, inhibitor/antagonist, Injections, Innovative Therapy, Institutes, interest, intravitreal injection, Investments, Literature, macrophage, macula, Measures, Mediating, Microglia, Mitochondria, Modeling, Mus, Natural Immunity, neuroprotection, Nonexudative age-related macular degeneration, novel, Oryctolagus cuniculus, Outcome, Oxidative Stress, Pathway interactions, Patient-Focused Outcomes, Patients, Peer Review, Peptides, Pharmaceutical Preparations, Pharmacologic Substance, Phase, phase 2 study, Phenotype, Photoreceptors, preclinical development, prevent, Proteins, Quality of life, recruit, Reproducibility, response, Retina, retinal damage, Retinal Detachment, Retinal Diseases, Role, Safety, safety study, Schedule, Signal Transduction, Small Business Technology Transfer Research, Social Impacts, Societies, Solid, Stress, Structure of retinal pigment epithelium, Testing, Therapeutic, Time, Toxicology, treatment strategy, United States, vector, Visual, Vitamins, Work | ONL THERAPEUTICS, INC., Ann Arbor, MI 48109, United States |
| 1R01DK126673-01 | Dong, Xinzhong, Yu, Shaoyong (Contact) | A Novel Mechanism of Mast Cell-Nerve Interactions in the Esophagus | R01 | 2020 | National Institute Of Diabetes And Digestive And Kidney Diseases | NIDDK | Project Summary Marked increases in esophageal mast cells (MCs) have been identified not only in allergic but also in non-allergic esophageal disorders. At present, their roles in the pathogenesis of those disorders are still less clear. Unlike intestinal mucosal MCs, esophageal MCs are predominantly distributed in the lamina propria of the mucosa, whereas they are matured in non-keratinized stratified squamous epithelium and developed into distinctive phenotype. Recently, the Immunologic Genome (ImmGen) Project Consortium has classified esophageal MC as one of the typical connective tissue MCs. Moreover, our new study has identified that MrgprB2 (the orthologue of human MrgprX2) is a GPCR and exclusively expressed in connective tissue MCs. Many basic secretagogues (substance P, VIP, PAMP, defensins, et al) and eosinophil cationic proteins are now known to activate mast cells exclusively via MrgprB2/X2 mechanisms. Our published and preliminary studies are supporting the novel hypothesis that MrgprB2 (MrgprX2 in human) mediates esophageal inflammation-induced MC activation and directly contributes to esophageal epithelial barrier dysfunction and esophageal afferent nociceptive nerve hyperexcitability. We will address this hypothesis in the mouse and human esophagus with following aims. In Aim 1, we will characterize MrgprB2-positive MCs in healthy and inflamed esophagus with respects to their distribution, phenotype, and activation response (mediators/cytokines release) to basic secrectagogues. We will then address the hypothesis that MrgprB2 mediates non-IgE-dependent MC activation by comparing MC mediator release in inflamed esophagus in wild type and MrgprB2mut mice. Lastly, we will explore, in an eosinophilic esophagitis model, whether eosinophil granule basic proteins (MBP, EPO, END,) directly activate MrgprB2. In Aim 2, we will continue to advance our interesting preliminary data demonstrating that reflux-induced esophageal epithelial barrier dysfunction (increased permeability) is significantly attenuated in MrgprB2 mut mice. To determine if non-MrgprB2 mast cell activation mechanisms also contribute to barrier breakdown we will compare permeability changes in our reflux vs allergic esophagitis models in three groups of mice, wild type mice; mice where the mast cells do not express functional MrgprB2 mut; and thirdly mice that are mast cell deficient. In Aim 3, we will compare the effect of MrgprB2 vs allergen-evoked mast cell activation on esophageal nociceptive C-fiber terminal activities using our well-established extra-cellular recording techniques along with our newly-developed two-photon neuron imaging methodology. In Aim 4, we will compare the expression and function of MrgprX2 in human esophageal biopsy specimens from reflux and eosinophilic esophagitis and then determine their correlations with esophageal histology/symptoms. Translationally, we will briefly characterize MrgprX2 expression and function in mouse esophagus by using our newly-established humanized MrgprX2 mouse line. Clarifying MrgprB2/X2-mediated esophageal mast cell activation may motivate investigation of novel targeted therapeutic strategies for esophageal inflammatory disorders. | Acids, Acute, Address, Allergens, Allergic, Attenuated, Biopsy Specimen, C Fiber, Cations, Chronic, Connective Tissue, cytokine, Cytoplasmic Granules, Data, Defensins, Disease, eosinophil, Eosinophil cationic protein, Eosinophil Granule Proteins, Eosinophilic Esophagitis, Epithelial, Epithelium, Esophageal Diseases, Esophagitis, Esophagus, experimental study, extracellular, Functional disorder, Funding, G-Protein-Coupled Receptors, Gastroesophageal reflux disease, Genome, Heartburn, Histology, Human, IgE, Image, immune activation, Immunologics, Inflammation, Inflammatory, Interleukin-5, Intestinal Mucosa, Investigation, Knowledge, Lamina Propria, Lead, Location, mast cell, Mediating, Mediator of activation protein, Methodology, Modeling, mouse model, mRNA Expression, Mucous Membrane, Mus, Nerve, Neuroimmune, Neurons, Neuropeptides, new therapeutic target, Nociception, novel, Pain, Pathogenesis, Peptic Esophagitis, Permeability, Phenotype, Play, Proteins, Publishing, Reaction, receptor, recruit, Reflux, Refractory, response, Role, Specimen, Stratified Squamous Epithelium, Substance P, Symptoms, Techniques, tissue injury, Tryptase, two-photon, Wild Type Mouse | Department of Internal Medicine/Medicine, JOHNS HOPKINS UNIVERSITY, Baltimore, MD 21218, United States |
| 1R01HL155107-01 | Loscalzo, Joseph | L-2-Hydroxyglutarate and Metabolic Remodeling in Hypoxia | R01 | 2021 | National Heart, Lung, And Blood Institute | NHLBI | Project Summary. Adaptive metabolic responses to hypoxia reflect essential evolutionary survival strategies in all eukaryotes. We recently identified a unique metabolite that increases in cardiovascular (CV) cells in response to hypoxia, L-2-hydroxyglutarate (L2HG). This metabolite is derived from ?- ketoglutarate, or 2-oxoglutarate (2OG), a key intermediate in the tricarboxylic acid cycle. Once formed from 2OG and NADH, L2HG has no other metabolic fate except to undergo oxidation back to 2OG by the stereospecific dehydrogenase, L2HG dehydrogenase (L2HGDH), suggesting that it accommodates (?buffers?) the increase in reducing equivalents accompanying hypoxia. L2HG has two other unique actions: it suppresses glycolysis and, as we show here, it increases pentose phosphate pathway (PPP) activity. The central hypothesis of this proposal is that L2HG suppresses glycolysis and enhances PPP activity in CV cells to eliminate reactive oxygen species (ROS), maintain cell redox potential, and preserve cell function in hypoxia. To address this hypothesis, we will focus on three specific aims. First, we will determine the molecular metabolic mechanisms underlying the effects of L2HG on glycolysis and PPP activity. In particular, we will focus on the unique role of a specific phosphofructokinase-2 isoform, PFKFB4, as a key regulatory determinant of increased flux through the PPP in hypoxia. Second, we will determine the effect of this L2HG-induced increased PPP activity in hypoxia on cellular redox potential and intra- and extracellular ROS elimination. Here, we will focus on PPP-derived NADPH and GSH as key cofactors in NADPH oxidase and glutathione peroxidase activities, respectively, in order to enhance elimination of excess ROS. Third, we will study the effects of L2HG in hypoxia or ischemia on cellular and cardiac function, respectively, using unique cellular and genetic murine models. Taken together, these studies should provide insights into the mechanisms by which L2HG promotes metabolic remodeling to preserve cell and cardiac function in oxygen-limited states. | 6-Phosphofructo-2-kinase, Address, Adverse effects, alpha ketoglutarate, Back, base, Biochemical, Brain Hypoxia-Ischemia, Buffers, cancer cell, Cardiac Myocytes, Cardiovascular Diseases, Cardiovascular system, Cell Hypoxia, cell injury, Cell physiology, Cells, Citric Acid Cycle, cofactor, Cultured Cells, cytotoxicity, Data, Dependence, Echocardiography, Endothelial Cells, Endothelium, Eukaryota, experimental study, extracellular, Fructose-2,6-bisphosphatase, Functional disorder, G6PD gene, Generations, Genetic, Glucose, Glutathione Disulfide, glutathione peroxidase, glutathione peroxidase GPX1, Glycolysis, Goals, GPX3 gene, Heart, heart function, Heterozygote, Homozygote, Human, Hypoxia, In Vitro, in vivo, inhibitor/antagonist, Injury, inorganic phosphate, insight, Ischemia, Knock-out, Lead, Mass Spectrum Analysis, Measures, Mediating, Metabolic, Metabolism, metabolomics, Molecular, mouse model, Mus, Myocardial, myocardial hypoxia, NADH, NADP, NADPH Oxidase, novel, Organ, overexpression, Oxidases, oxidation, Oxidation-Reduction, Oxides, Oxidoreductase, Oxygen, Pentosephosphate Pathway, Perfusion, Pharmacology, Preparation, preservation, Protein Isoforms, Reaction, Reactive Oxygen Species, Reperfusion Therapy, response, Role, Small Interfering RNA, small molecule, Stress, Testing, Time | BRIGHAM AND WOMEN'S HOSPITAL, Boston, MA 02115, United States |
| 1R01EY032057-01 | Wright, Kevin | Transcriptional control of retinal neuron specification and maturation. | R01 | 2021 | National Eye Institute | NEI | PROJECT SUMMARY/ABSTRACT Amacrine cells (ACs) are the principle inhibitory neurons of the inner retina, with at least 45 morphologically distinct subtypes that can be distinguished by the size, shape, and stratification of their dendritic arbors within the inner plexiform layer (IPL). Most ACs do not have axons, and instead integrate signaling across their dendritic arbors. This unique arrangement means that form and function are intimately related in ACs, perhaps more so than in any other neuron type. However, we know virtually nothing about how individual AC subtypes are specified during development, or how their adopt their stereotyped morphologies. We hypothesize that selectively expressed transcription factors (TFs) are well poised to direct subtype-specific genetic programs that specify and direct the morphological maturation of ACs. Within the AC population, the homeodomain TF Isl1 is only expressed in starburst amacrine cells (SACs) and Gbx2 is only expressed in a previously unidentified population of medium-field non-GABAeric, non-Glycinergic ACs (MF-nGnGs). Our preliminary results show that early deletion of Isl1 or Gbx2 from AC precursors results in defects in SAC and MF-nGnG subtype specification, respectively. Later deletion of Isl1 or Gbx2 in post-migratory SACs or MF-nGnGs alters their dendritic morphology and stratification patterns. Therefore, Isl1 and Gbx2 appear to be required for the initial specification and the subsequent morphological maturation of their respective AC subtypes. We will test this in the following Specific Aims: 1) Determine whether Isl1 and Gbx2 are necessary and sufficient for AC subtype specification and maturation. We will use conditional loss- and gain-of function approaches to determine whether Isl1 and Gbx2 are both necessary and sufficient to initiate and maintain terminal differentiation in SACs and MF-nGnGs, respectively. Furthermore, we will use a combination of genomic approaches (RNASeq, ATACseq) to identify the Isl1 and Gbx2 gene regulator networks in the respective AC subtypes. 2) Define how Isl1 and Gbx2 regulate SAC and MF-nGnG morphology and functional connectivity. We will first identify how the loss of Isl1 in SACs and Gbx2 in MF-nGnGs affects the development of their stereotyped dendritic morphology and stratification patterns. Then we will test candidate effector genes and pathways for their involvement in the establishment of dendritic arbors. Finally, we will determine how the loss of Isl1 and Gbx2 affects the functional connectivity of SACs and MF-nGnGs in visual circuits. Together, these experiments are expected to reveal how selectively expressed transcription factors specify AC subtypes and drive terminal differentiation programs that endow ACs with their unique morphological properties. We expect that these findings will reveal principles that are broadly applicable across the developing nervous system. | Adopted, Affect, Amacrine Cells, ATAC-seq, Axon, base, Biological Models, Cell Surface Receptors, Cells, cellular imaging, Cellular Morphology, Chromatin, Complex, Data, Defect, Development, Disease, Electrophysiology (science), experimental study, gain of function, Genes, Genetic, Genetic Transcription, Genomic approach, Goals, homeodomain, Individual, inhibitory neuron, Injury, Inner Plexiform Layer, insight, Molecular, Morphology, Nervous system structure, neural circuit, Neurons, novel, Pathway interactions, Pattern, Population, Preparation, Process, programs, Property, public health relevance, receptor, regenerative therapy, Regulator Genes, Retina, retinal neuron, Role, selective expression, Shapes, Signal Transduction, single cell sequencing, Specific qualifier value, starburst amacrine cell, Stereotyping, Stratification, Testing, To specify, transcription factor, Transcriptional Regulation, transcriptome sequencing, virtual, Visual | OREGON HEALTH & SCIENCE UNIVERSITY, Portland, OR 97239, United States |
| 3R01MH118695-03S1 | Adali, Tulay, Calhoun, Vince D (Contact) | Male/Female differences in psychosis and mood disorders:Dynamic imaging-genomic models for characterizing and predicting psychosis and mood d | R01 | 2020 | National Institute Of Mental Health | OD | Disorders of mood and psychosis such as schizophrenia, bipolar disorder, and unipolar depression are incredibly complex, influenced by both genetic and environmental factors, and the clinical characterizations are primarily based on symptoms rather than biological information. Current diagnostic approaches are based on symptoms, which overlap extensively in some cases, and there is growing consensus that we should approach mental illness as a continuum, rather than as a categorical entity. Since both genetic and environmental factors play a large role in mental illness, the combination of brain imaging and genomic data are poised to play an important role in clarifying our understanding of mental illness. However, both imaging and genomic data are high dimensional and include complex relationships that are poorly understood. To characterize the available information, we are in need of approaches that can deal with high-dimensional data exhibiting interactions at multiple levels (i.e., data fusion), while providing interpretable solutions (i.e., a focus on brain and genomic networks). An additional challenge exists because the available data has mixed temporal dimensionality, e.g., single nucleotide polymorphisms (SNPs) do not change over time, brain structure changes slowly over time, while fMRI changes rapidly over time. To address these challenges, we introduce a new unified framework called flexible subspace analysis (FSA) that subsumes existing models while providing important extensions. FSA can automatically identify subspaces (groupings of unimodal or multimodal components) in joint multimodal data. Our approach leverages the interpretability of source separation approaches and can include additional flexibility by allowing for a combination of both linear and nonlinear (shallow and deep) subspaces. We will apply the developed models to a large (N~80,000) dataset including individuals along the mood and psychosis spectrum to evaluate the important question of disease categorization. We will compute fully cross-validated genomic-neuro-behavioral profiles of individuals including a comparison of the predictive accuracy of 1) standard categories from the diagnostic and statistical manual of mental disorders (DSM), 2) data-driven subgroups, and 3) dimensional relationships. We will also evaluate the single subject predictive power of these profiles in independent data to maximize generalization. All methods and results will be shared with the community. The combination of advanced algorithmic approach plus the large N data promises to advance our understanding of the nosology of mood and psychosis disorders in addition to providing new tools that can be widely applied to other studies of complex disease. | 3-Dimensional, Address, Algorithms, base, Biological, Biological Markers, Bipolar Disorder, Brain, Brain imaging, Categories, Clinical, Cognitive, Communities, Complex, Consensus, Data, data fusion, Data Set, Diagnosis, Diagnostic, Diagnostic and Statistical Manual of Mental Disorders, Diffusion Magnetic Resonance Imaging, Dimensions, Disease, disease classification, Environmental Risk Factor, Exhibits, Female, flexibility, Functional Magnetic Resonance Imaging, Genetic, genomic data, Genomics, Goals, Grouping, Image, Individual, Joints, male, Measures, meetings, Mental disorders, Methods, Modeling, Mood Disorders, Moods, multidimensional data, multimodal data, multimodality, neurobehavioral, novel, Play, Psychotic Disorders, Role, Schizophrenia, Services, sex, Single Nucleotide Polymorphism, Source, Structure, Subgroup, Symptoms, task analysis, Time, tool, Unipolar Depression | Department of Psychology, GEORGIA STATE UNIVERSITY, Atlanta, GA 30302, United States |
| 1R01DK126710-01 | Tang, Minghua | Dietary influence on infant growth and the gut microbiota | R01 | 2021 | National Institute Of Diabetes And Digestive And Kidney Diseases | NIDDK | The overall objective of this project is to establish how infant diet with different protein-rich foods regulate growth trajectories and gut microbiota development. Both NIH and USDA are now addressing the urgent need for evidence-based dietary guidance early in life, particularly regarding protein intake, but a significant knowledge gap exists in the effects of protein-rich foods on growth and development during early complementary feeding. Early complementary feeding (~5 to 12 months of age), when infants start to consume foods beyond breastmilk or formula, is a critical transition period of developmental plasticity. Growth trajectories and shifts of the gut microbiota during this critical period have the potential to program long-term body weight, composition and disease risks and are greatly influenced by diet. Preliminary data from our pilot study in formula-fed infants demonstrated that consuming diets with two protein-rich foods: meat and dairy at a high-intake level, resulted in distinctive growth patterns from 5 to 12 months of age. An important new preliminary finding was that meat- and dairy-based foods directly affected gut microbiota diversity, composition and short-chain fatty acid production at 12 months. Changes in gut microbiota composition were also associated with infant linear growth (length gain). Here we propose three specific aims to determine how the introduction of common protein-rich foods impact infant growth (Aim 1), the development of gut microbiota (Aim 2) and the relationship between gut microbiota and infant growth (Aim 3), in a randomized controlled trial. Healthy, term infants (n=300) will be recruited and randomized to meat-, dairy-, plant-based diet groups or the reference group (standard of care), from 5 to 12 months. We will use controlled feeding (all foods provided, and formula if needed) with longitudinal assessments of gut microbiota, infant growth, blood biomarkers (IGF-1, IGFBP3, insulin, amino acids, lipids, etc.), dietary intakes, body composition, and total energy expenditure. Our multi-disciplinary team is ideally positioned to conduct this project, with collective expertise in pediatric nutrition, human clinical trials, microbiome, biostatistics, and a long-standing record of collaboration. Findings are expected to have significant scientific and health implications for determining dietary patterns that promote optimal infant growth and identifying gut microbial changes that are beneficial to the host metabolism and growth during early complementary feeding. The results of the study will also support evidence-based dietary recommendations in infants to prevent the risk of overweight and later obesity. | Address, Adult, Affect, Age, age group, Age-Months, Amino Acids, Bacteria, base, Biological Markers, Biometry, Blood, Body Composition, Body Weight, Breast, Butyrates, Child Nutrition, Clinical, Clinical Trials, Collaborations, Complementary Feeding, Consumption, critical period, Dancing, Data, Development, developmental plasticity, Diet, Dietary intake, Dietary Intervention, Dietary Practices, disorder risk, Evaluation, evidence base, feeding, Food, food consumption, Genes, Goals, Growth, Growth and Development function, gut microbiota, Health, Human, Human Milk, IGFBP3 gene, infancy, Infant, Inflammation, Insulin, Insulin-Like Growth Factor I, Intake, Intervention, Knowledge, Length, Life, Lipids, Marketing, Measures, Meat, Mediating, Mediation, Metabolism, Metagenomics, microbial, microbiome, microbiota, Modeling, multidisciplinary, novel, Obesity, obesity in children, Overweight, Pathway interactions, Pattern, Pilot Projects, Plants, Positioning Attribute, prevent, Production, programs, protein intake, Proteins, Public Health, Race, Randomized, Randomized Controlled Trials, Recommendation, recruit, Research, Risk, Ruminococcus, sex, standard of care, total energy expenditure, United States National Institutes of Health, Volatile Fatty Acids, Weight, Weight Gain | Department of Pediatrics, UNIVERSITY OF COLORADO DENVER, Aurora, CO 80045, United States |
| 1S10RR026516-01 | Batey, Robert T | Purchase of an Isothermal Titration Calorimeter | S10 | 2010 | National Center For Research Resources | NCRR | DESCRIPTION (provided by applicant): This shared instrumentation grant program proposal requests funds for the purchase of a state-of-the-art isothermal titration microcalorimeter (ITC). Calorimetry provides a wealth of information about macromolecular interactions and enzymatic kinetics by measuring the heats of reaction. This technique has distinct advantages over others, including that it can obtain information about the binding affinity, enthalpy and entropy of reaction and stoichiometry of the reaction in a single experiment and that it does not require the labeling of either the titrant or titrate molecules. Recent advances in instrumentation also allow for 10-fold lower sample amounts to be used per experiment and significantly decreased run time as compared to previous generation instruments. These considerations make this technique accessible to a broader spectrum of users and facilitates overall higher throughput, which are important features for shared instrumentation. Acquisition of the proposed MicroCal iTC200 would facilitate research programs directly related to human health issues in a number of important ways. Major users of this instrument propose to use this instrument to investigate the regulatory mechanisms of kinases involved in a variety of key cellular signal transduction pathways in humans (Prof. Natalie Ahn), RNA-based regulatory elements that directly sense cellular metabolites (Prof. Robert Batey), a nucleic acid aptamer that is an FDA- approved drug to fight macular degeneration (Prof. Arthur Pardi), and the nature of protein-DNA interactions at the end of linear chromosomes (Prof. Deborah Wuttke). These research goals along with those of the minor users emphasizes the strength of biophysics and biochemistry at the University of Colorado, Boulder and the proposed instrument would fulfill a core need of a large community of users. | Affinity, aptamer, Arts, base, Binding (Molecular Function), Biochemistry, Biophysics, Calorimetry, Chromosomes, Colorado, Communities, DNA-Protein Interaction, enthalpy, Entropy, FDA approved, fighting, Funding, Generations, Goals, Grant, Health, Heating, Human, instrument, instrumentation, Kinetics, Label, Macular degeneration, Measures, Minor, Nature, Nucleic Acids, Pharmaceutical Preparations, Phosphotransferases, programs, Reaction, Regulatory Element, Request for Proposals, Research, research study, Running, Sampling, Signal Transduction Pathway, stoichiometry, Techniques, Time, Titrations, Universities | Department of Chemistry, UNIVERSITY OF COLORADO, Boulder, CO 80303, United States |
| 3K01MH117442-04S1 | Ho, Tiffany Cheing | The Roles of Inflammatory and Glutamatergic Processes in the Neurodevelopmental Mechanisms Underlying Adolescent Depression | K01 | 2020 | National Institute Of Mental Health | NIMH | PROJECT SUMMARY First episodes of major depressive disorder (MDD) typically begin during adolescence. Despite the fact that adolescent-onset MDD is associated with more severe and recurrent episodes of MDD, little work has been done to identify mechanisms underlying depressive relapse or recurrence. Prior work by the candidate has documented differences in functional and structural connectivity involving the anterior cingulate cortex (ACC) between adolescents with MDD and psychiatrically healthy controls; these phenotypes are posited to reflect altered neurodevelopment in key emotion regulation circuitry. We do not yet know, however, whether and how MDD impacts adolescent development of ACC connectivity in a manner that contributes to an increased risk of depressive relapse or recurrence. One mechanism may be the immune system, which activates in response to psychosocial stressors and influences neurotransmitter systems including glutamate, the primary excitatory neurotransmitter in the brain. Basic research indicates that higher levels of pro-inflammatory cytokines leads to overexcitation of glutamatergic neurons to the point of neurotoxicity and, consequently, to reduced neuroplasticity. Further, neuroimaging studies of adult MDD have reported heightened levels of inflammation and altered levels of glutamate in the ACC. These data, combined with growing evidence that ACC connectivity undergoes extensive maturation during adolescence, suggest that heightened inflammation and excessive glutamate may lead to atypical development of this circuitry in adolescents with MDD. The candidate therefore seeks to test the central hypothesis that heightened inflammation acts through glutamate transmission to disrupt typical neurodevelopment of ACC connectivity in adolescents with MDD to increase risk of depressive relapse or recurrence. This K01 will test this model in 60 adolescents with first episodes of MDD assessed longitudinally over 3 time points using an innovative multimodal approach. The candidate will assay peripheral levels of pro-inflammatory cytokines using dried blood spot technology, noninvasively image glutamate and antioxidants in ACC using proton magnetic resonance spectroscopy, and assess neurodevelopmental changes of ACC connectivity using functional (resting-state fMRI) and structural (diffusion MRI) methods. This K01 fills key gaps in our understanding of whether adolescent MDD impacts development of ACC connectivity, how inflammatory and glutamatergic mechanisms underlying MDD-related changes in ACC connectivity contribute to subsequent relapse or recurrence in adolescents with MDD, and whether antioxidants protect against depression recurrence by buffering the effects of inflammation on adolescent development of ACC circuitry. Importantly, the candidate will execute this research in the context of receiving advanced training in stress-related immune biology, causal inference modeling, and developmental psychopathology. Results from this project will culminate in an R01 that aims to identify subtypes/biotypes of adolescent MDD based on clinical course and multimodal characterizations of brain trajectories. | Adolescence, Adolescent, adolescent brain development, Adolescent Development, Adult, Affect, Age, Anterior, Antioxidants, associated symptom, base, Basic Science, Biological Assay, Biology, Blood, Brain, Buffers, Cell membrane, child depression, Chronic, cingulate cortex, Clinical, cytokine, Data, depressive symptoms, Development, Diffusion Magnetic Resonance Imaging, Disease, emotion regulation, Emotions, epidemiologic data, Exhibits, experience, Formulation, Functional Magnetic Resonance Imaging, Glutamates, Goals, Image, Immune, Immune system, improved, Inflammation, Inflammatory, inflammatory marker, innovation, Intervention, Lead, Light, Longitudinal Studies, Magnetic Resonance Spectroscopy, Major Depressive Disorder, Measures, Mediating, Mental Depression, Mental Health, Methods, Modeling, Morbidity - disease rate, multimodality, neurobiological mechanism, Neurobiology, neurodevelopment, neuroimaging, Neuronal Plasticity, Neurons, neurotoxicity, Neurotransmitters, non-invasive imaging, Onset of illness, peer, Peripheral, personalized intervention, Phenotype, physical conditioning, Prefrontal Cortex, Process, Protons, Psychopathology, psychosocial, Public Health, public health relevance, Recurrence, recurrent depression, Refractory, Relapse, relapse prediction, relapse risk, Reporting, Research, response, Rest, Risk, Role, Severities, single episode major depressive disorder, Spottings, Stress, stressor, Structure, System, Technology, Testing, tetrahydrobiopterin, Time, Training, transmission process, white matter, Work | Department of Psychiatry, UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, San Francisco, CA 94143, United States |
| 1R21MH124678-01 | Hightow-Weidman, Lisa B (Contact), Horvath, Keith Joseph | Using EMA to developmentally tailor an intervention to support on-demand PrEP among YMSM | R21 | 2020 | National Institute Of Mental Health | NIMH | Project Abstract Adolescent and young adult men who have sex with men (YMSM) bear a heavy burden of HIV in the United States (US). Despite the availability of highly effective daily oral HIV pre-exposure prophylaxis (PrEP), uptake and adherence to PrEP among YMSM remains low. The challenge of taking a daily pill, as well as concerns regarding side effects of the medication, have been identified as reasons for lower than expected uptake of PrEP among youth, and particularly YMSM of color. On-demand, or event-driven, PrEP has been shown to be effective among adult MSM but, to date, has not been examined among YMSM. Data from the extant literature support that YMSM with and without experience with PrEP show interest in exploring different dosing strategies. This interest may translate into greater uptake of PrEP, particularly among those who have expressed unwillingness to try a daily regimen or have not been successful adhering to a daily regimen. While preliminary evidence from adolescent treatment studies suggests that intermittent regimens may be feasible for youth, their ongoing executive function development, coupled with heightened responsiveness to socioemotional contexts, has implications for decision making around sexual behavior and preventative health care. In addition, traits common in adolescents ? including impulsivity and sensation seeking - have demonstrated significant and meaningful associations with behaviors that place YMSM at risk for HIV. For these reasons, variable ?on demand? strategies may be challenging for youth who are still developing cognitively, and, require developmentally appropriate interventions to maximize their success. While studies of on-demand PrEP strategies have shown that adult MSM have difficulties accurately predicting when sex will occur, this has not been explored among YMSM. The proposed study fills these important gaps in understanding to guide future on-demand PrEP interventions with YMSM. This study will provide insights into potential developmental barriers to on-demand PrEP among YMSM and lay the groundwork for an innovative intervention approach to address them through the completion of three specific aims. Specific Aims 1 and 2 will provide a greater understanding of developmental and cognitive facilitators and barriers to on-demand PrEP. To accomplish these aims, a sample of 120 youth (age 16-24 years) will be recruited and complete a daily electronic diary for 8 weeks to record their predictions of, and actual engagement in, sexual encounters. Surveys conducted at baseline and study completion will measure developmental and sociocultural factors likely to impact prediction of risk (e.g. executive function, impulsivity, planning), and potential intervention approaches (e.g. gist vs. verbatim messages, reward sensitivity). Focus groups conducted in Aim 3 will help to translate findings from Aims 1 and 2 into a just-in-time intervention to increase YMSM's ability to plan for sexual activity and incorporate PrEP dosing based on accurate risk perception. Youth Advisory Board meetings will take place to provide feedback on intervention design. | Address, Adherence, Adolescence, Adolescent, Adolescent and Young Adult, Adult, Age, AIDS prevention, base, Behavior, Brain, Caring, Chronic Disease, Cities, Cognitive, cognitive neuroscience, Color, Coupled, Data, Decision Making, Development, Diagnosis, diaries, Dose, Epidemic, Esthesia, Event, executive function, experience, Feedback, Focus Groups, Future, Goals, HIV, HIV diagnosis, improved, Impulsivity, innovation, insight, interest, Intervention, Literature, Measures, medication compliance, meetings, men, men who have sex with men, Modality, Modeling, oral HIV, Pharmaceutical Preparations, pill, Play, pre-exposure prophylaxis, Prevention, Preventive healthcare, Preventive Intervention, recruit, Regimen, Research, response, Rewards, Risk, risk perception, Role, Sampling, sex, Sex Behavior, sexual encounter, side effect, social culture, success, Surveys, theories, therapy design, Time, trait, Translating, treatment adherence, United States, uptake, Ursidae Family, young adult, young men who have sex with men, Youth | Department of Internal Medicine/Medicine, UNIV OF NORTH CAROLINA CHAPEL HILL, Chapel Hill, NC 27599, United States |
| 1R03AG069816-01 | Chung, Jane | Voice2Connect: Informing the Design of Smart Speakers for Social Connectedness in Low-Income Older Adults | R03 | 2020 | National Institute On Aging | NIA | Project Summary/Abstract There is a growing public health concern regarding the high risk of social isolation and loneliness among low- income older adults and its resulting impact on their longevity and overall well-being. The issue of social isolation is particularly relevant to low-income senior housing (LISH) residents who often have multiple chronic conditions and disabilities, lack of financial and social resources, and limited social networks. Thus, there is an urgent need to develop innovative approaches to mitigate these issues in older adults living in LISH. Voice- operated smart speakers have the potential to reduce social isolation and loneliness in this population, for example, by connecting with other people, sending a reminder about social activities, or providing a conversational agent. The hands-free voice control provides improved accessibility and usability for people with low literacy, vision impairment, mobility limitation, or poor dexterity issues. We propose to examine how smart speakers can support the needs of social connectedness among older adults living alone in LISH. We will use an iterative user-centered design and employ a mixed-methods approach, incorporating participatory methods, focus group interviews, and functional and psychosocial health questionnaires. The specific aims of this study are: (1) to determine experiences of social isolation, user needs, user context, and preferences related to the use of smart speakers for social connectedness in the LISH setting, (2) to evaluate older adults (smart speaker users and non-users)? and stakeholders? attitudes towards the in-home use of smart speakers for promoting social engagement, with a focus on perceived usability and usefulness of the technology, and (3) to identify potential implementation barriers and privacy concerns among older adults and stakeholders. Stakeholders will include housing staff members (N=10) and health care professionals (N=6) providing wellness services to LISH residents. Older adults (N=36) will form six focus groups and take part in a series of three focus group sessions in which they participate in user-centered design activities to identify potential smart speaker features that can support the needs of social connectedness. Their thoughts and ideas will be used to develop low-fidelity prototypes and scenarios of use for each prototype. After prototype and scenario development, we will seek input from the older adults, housing staff, and health care providers through focus groups, which will be used to refine the prototype. The refined prototypes will be validated with the older adult participants. We will use a thematic analysis and inductive coding method to analyze focus group interview transcripts. Descriptive statistics will be used to analyze the questionnaire data collected from older adults and stakeholders. Findings from this study will inform our future research where we build smart speaker algorithms and functionalities that can facilitate the planning of innovative smart speaker-based social connectedness interventions for older adults in LISH. | Address, Adoption, Age, Aging, Algorithms, Artificial Intelligence, Attitude, base, Caring, Chronic, Clinic, Code, cognitive function, Communities, community living, Computers, cost, Data, design, Development, dexterity, disability, Elderly, Environment, Exhibits, experience, Feedback, Focus Groups, Funding, Future, Group Interviews, Hand, Health, Health Personnel, Health Professional, high risk, Home environment, Housing, Human, improved, Independent Living, Individual, innovation, innovative technologies, intelligent personal assistant, Intervention, Knowledge, Leisure Activities, literacy, Loneliness, Longevity, Low income, Medical, member, Mental Depression, Methods, Modeling, Morbidity - disease rate, mortality, multiple chronic conditions, Names, Outcome, Participant, Perception, Personal Satisfaction, Population, preference, Privacy, prototype, psychosocial, Public Health, Quality of life, Questionnaires, Research, Resources, Series, Services, Site, social, social capital, social engagement, Social isolation, Social Network, Social support, Staff Attitudes, statistics, success, System, Systems Development, Technology, Testing, Thinking, tool, Transcript, Transportation, Universities, usability, user centered design, Virginia, virtual, Visual impairment, Voice, Wellness Program, Work | Department of Other Health Professions, VIRGINIA COMMONWEALTH UNIVERSITY, Richmond, VA 23298, United States |
| 1R01LM013509-01 | Cooper, Gregory F. | Automated Surveillance of Overlapping Outbreaks and New Outbreak Diseases | R01 | 2021 | National Library Of Medicine | NLM | Project Summary / Abstract This project will develop and evaluate new methods for automated detection and characterization of infectious respiratory diseases. The methods will be novel in their ability to detect and characterize (1) multiple, overlapping outbreaks of known diseases, which is a situation that occurs commonly, (2) an outbreak of a new, emerging disease, which can be dangerous, and (3) a combination of 1 and 2 occurring at the same time. The ability to detect a new disease early, in the context of other common outbreaks occurring, may be particularly important if the disease causes serious illness and spreads rapidly in the population. The new methods can also use a wide variety of data to perform outbreak detection and characterization, including emergency department reports, laboratory results, retail thermometer sales in the region, and local health-related tweets. These new methods will be built upon the framework of an existing Bayesian, probabilistic system, which the investigators have developed. This system takes as input data used to perform outbreak detection and characterization, and it outputs the probabilities of different possible disease outbreaks that may be occurring, as well as their characteristics, such as their probable start times and epidemiological curves. A unique aspect of the system is its ability to use data from individual patient clinical reports, such as emergency department reports. The system applies natural language processing to the reports to derive a set of symptoms, signs, and other findings. It then uses these findings and probabilistic disease models to derive a probability distribution over the diseases for each patient. For the many patients seen in the recent past, the system uses their probability distributions as evidence in detecting and characterizing disease outbreaks. The project will be evaluated using simulated data and real data from Allegheny County, Pennsylvania. It will focus on four common outbreak diseases, namely, influenza A, influenza B, respiratory syncytial virus (RSV), and adenovirus. The evaluation will examine how well the system can (1) detect and characterize multiple overlapping outbreaks of disease, (2) detect a new outbreak disease and create an accurate clinical description of it (using a leave-one-out cross validation approach), and (3) use a variety of data types to improve outbreak detection and characterization. The innovation being advanced by this research is a novel, integrated, probabilistic approach for the early and accurate detection of disease outbreaks that threaten public health. The proposed approach has significant potential to improve the information available to clinicians and public health officials, which can be expected to improve clinical and public health decision making, and ultimately to improve population health. | Accident and Emergency department, Adenoviruses, Algorithms, Caring, Characteristics, Clinical, Communicable Diseases, County, Couples, Dangerousness, Data, Data Set, Decision Making, Detection, Diagnosis, Disease, Disease model, Disease Outbreaks, Disease Surveillance, emerging pathogen, Epidemiology, Evaluation, Health, Healthcare Systems, Human, Humidity, improved, Individual, individual patient, Influenza, Influenza A virus, Influenza B Virus, influenza outbreak, innovation, Laboratories, Logistics, Lung diseases, Masks, Methods, Modeling, Morbidity - disease rate, mortality, Natural Language Processing, novel, Output, pathogenic virus, Patients, Pennsylvania, Performance, Population, population health, Probability, Public Health, Reporting, Research, Research Personnel, Research Support, respiratory, respiratory pathogen, Respiratory syncytial virus, Sales, Stress, Symptoms, System, Testing, Thermometers, Time, Validation | UNIVERSITY OF PITTSBURGH AT PITTSBURGH, Pittsburgh, PA 15213, United States |
| 2P50DC014664-06A1 | Fridriksson, Julius | Telerehab for Aphasia (TERRA) | P50 | 2021 | National Institute On Deafness And Other Communication Disorders | NIDCD | Summary: Project 1 It is now commonly accepted that aphasia therapy in chronic stroke is effective for improving language processing, and perhaps to a lesser extent, quality of life. Nevertheless, most persons with chronic aphasia in the United States have very limited access to therapy. Although the reasons for this state of affairs are several, two factors are particularly important: insufficient reimbursement for therapy services and lack of access to local transportation to and from therapy. A way to tackle both of these problems is to provide aphasia therapy at a lower cost and eliminate the need for transportation. Providing aphasia therapy via telemedicine (clinician administered therapy across the internet) will provide cheaper therapy by eliminating the need for a physical facility to provide services and by reducing the need for transportation to and from therapy for either the clinician (home health) or the patient (outpatient clinic). The purpose of Project 1 is to conduct a phase II, non- inferiority trial of telerehab for aphasia therapy (aphasia remote therapy; ART), which will be exclusively administered by a speech-language pathologist. All participants (N=100) will be randomized to receive either telerehab (ART) or in-clinic therapy (I-CT) using the same kind of therapy we are currently using in Project 1. The outcome measure will focus on speech production and combines correct naming and correct words produced per minute during discourse. The primary endpoint is change in the outcome measure at 6 months compared to baseline. The non-inferiority margin will be set so that if ART leads to less than 50% improvement than the improvement following I-CT, it will be considered inferior for therapy delivery. In addition to comparing the difference in outcome for ART and I-CT, we will also explore factors that influence the efficacy of telerehab for aphasia therapy. For this purpose, we use a theoretical framework that is typically used to study the acceptance of and personal attitudes towards telemedicine. Moreover, we will test participants? cognitive- linguistic status and collect biographical information to study which participants may have difficulty with telerehab and may be poor candidates in a future, phase III trial. If our trial finds that ART is non-inferior to I- CT, it will provide strong motivation to proceed with a phase III trial on a therapy modality that could significantly alter and improve access to aphasia therapy for a population that now is estimated to exceed 2 million individuals in North America. In addition to conducting a very timely clinical trial on ART, the work proposed here will continue to expand our database on aphasia therapy outcome that is being populated in the current phase of Project 1. Accordingly, the synergy between the current and the proposed work in Project 1 will be maintained. Moreover, Project 1 will continue to provide data for Projects 3 and 4 to study brain health in relation to aphasia therapy outcome and neuropsychological models of language, respectively. | Acute, Adopted, Affect, Ambulatory Care Facilities, Aphasia, aphasia recovery, Attitude, Biography, brain health, Caring, Case Study, Chronic, chronic stroke, Clinic, Clinical Trials, Cognitive, Communication, comparative efficacy, computerized, cost, Data, Databases, disability, Effectiveness, Enzyme-Linked Immunosorbent Assay, executive function, Future, Goals, Health, Home environment, Improve Access, improved, Individual, Inferior, Internet, Language, language processing, Language Therapy, Linguistics, Logistics, Medical, Meta-Analysis, Modality, Modeling, Motivation, Names, Neuropsychology, North America, Outcome, Outcome Measure, Participant, Pathologist, Patients, Personal Computers, personalized predictions, Persons, Phase, phase III trial, Philadelphia, phonology, Physical therapy, Policies, Population, pre-clinical, predicting response, primary endpoint, Production, Provider, Quality of life, Randomized, Recovery, rehabilitation service, Rehabilitation therapy, Research, rural area, Semantics, Services, Severities, Source, Speech, Speech Therapy, Stroke, stroke outcome, stroke recovery, stroke-induced aphasia, Supervision, synergism, Technology, technology validation, Telemedicine, telerehabilitation, Testing, therapy outcome, Third-Party Payer, Time, Transportation, United States, Work | UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA, Columbia, SC 29208, United States |
| 1R35NS122339-01 | Wechsler-Reya, Robert J | Identifying and Targeting the Drivers of Pediatric Brain Tumors | R35 | 2021 | National Institute Of Neurological Disorders And Stroke | NINDS | PROJECT SUMMARY Medulloblastoma is the most common malignant brain tumor in children. Although aggressive treatments have improved outcomes, many patients still die of their disease, and survivors suffer severe long-term side effects from the therapy. Thus, safer and more effective approaches to therapy are critical. In our previous studies we have created new animal models of medulloblastoma and used them to define cells of origin, identify key regulators of tumor initiation and maintenance, and uncover agents that may be effective for therapy of the disease. Although we have made important strides over the last few years, there are a number of critical questions that remain unanswered. In the coming years, we will take advantage of the models and approaches we have developed to: (1) Identify drivers and create models for the deadliest forms of medulloblastoma; (2) Uncover the molecular mechanisms of leptomeningeal metastasis, and find novel strategies for targeting metastatic disease; (3) Use primary patient tumors as a platform to discover new therapies; and (4) Identify mechanisms that regulate immune responses to medulloblastoma. The overall goal of our research is to gain a deeper understanding of medulloblastoma biology and use this information to develop more effective approaches to therapy. Although these studies are ambitious, they are essential if we are to make a difference in the lives of children with this devastating disease. | aggressive therapy, Animal Model, Biology, Cells, Child, Childhood Brain Neoplasm, Critical Pathways, Disease, effective therapy, Goals, Growth, Immune response, improved outcome, Maintenance, Malignant neoplasm of brain, medulloblastoma, Metastatic Neoplasm to the Leptomeninges, Modeling, Molecular, novel strategies, novel therapeutics, Patients, Pediatric Neoplasm, Research, side effect, Survivors, tumor, tumor initiation | SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE, La Jolla, CA 92037, United States |
| 1R01DK126786-01 | Burrage, Lindsay C | DISSECTING THE LINK BETWEEN UREAGENESIS AND HEPATIC GLYCOGEN METABOLISM | R01 | 2021 | National Institute Of Diabetes And Digestive And Kidney Diseases | NIDDK | PROJECT SUMMARY/ABSTRACT Urea cycle disorders (UCDs) are common inborn errors of hepatic metabolism. With improved therapies such as nitrogen-scavenging agents to prevent elevated ammonia levels, patients with UCDs have increased survival. However, even in the absence of hyperammonemia, patients with UCDs may have chronic liver disease. Liver disease in UCDs can manifest as abnormal serum transaminases, hepatomegaly, hepatic fibrosis, or hepatocellular carcinoma. Among the UCDs, the highest prevalence of chronic liver disease occurs in argininosuccinate lyase deficiency (ASLD). Importantly, the cause for liver disease in UCDs such as ASLD is unknown, and liver disease has not been prevented by standard therapies. Moreover, there are no therapeutic strategies specifically targeting liver disease in ASLD or other UCDs. One common histopathologic finding in ASLD and other UCDs is excess hepatic glycogen deposition. However, the mechanism underlying hepatic glycogen accumulation and its consequences on hepatic function in UCDs are unknown. Hepatic glycogen deposition is associated with liver disease in glycogen storage disorders and diabetic glycogenic hepatopathy. Thus, our central hypothesis is that urea cycle dysfunction and accumulation of ammonia and other toxic metabolites disrupt hepatic energy metabolism, including glycogen metabolism, and cause liver disease in UCDs. Studies using current mouse models of ASLD and other distal UCDs have been complicated by the small size and shortened lifespan. To overcome this challenge and facilitate our proposed studies, we have manipulated mouse models of ASLD and citrullinemia to extend the lifespan and improve growth. For the proposed studies, we will use biochemical studies, genetic manipulation and stable isotope studies in these mouse modes to address the following questions: 1) What is the biochemical basis of hepatic glycogen accumulation in ASLD? 2) Does normalization of hepatic glycogen levels prevent liver disease in ASLD? Insights from these studies have the potential to have significant impact on our understanding of the relationship between urea cycle dysfunction and hepatic glycogen metabolism. In addition, the results may inform chronic management strategies for patients with UCDs and may lend insights into new treatment approaches for this group of disorders. On broader terms, our studies may elucidate mechanisms that contribute to the regulation of hepatic glucose flux in more common disorders of glucose metabolism. | Acetylation, Address, Adenoviruses, Alpha-glucosidase, Ammonia, Argininosuccinate lyase deficiency, Biochemical, Birth, Chronic, chronic liver disease, Cirrhosis, Citrullinemia, comorbidity, Complication, Data, Deposition, Diabetes Mellitus, diabetic, Disease, Distal, Early Diagnosis, Energy Metabolism, enzyme activity, Enzymes, Functional disorder, Generations, genetic manipulation, Genetic Transcription, Glucose, Glucose Metabolism Disorders, glucose output, Glycogen, Glycogen (Starch) Synthase, glycogen metabolism, Glycogen Phosphorylase, glycogenolysis, Growth, Hepatic, Hepatic Tissue, Hepatomegaly, Hereditary Disease, High Prevalence, Human, human tissue, Hyperammonemia, Impairment, improved, Individual, Infant, insight, Life, Link, Liver, Liver Cirrhosis, Liver diseases, Liver Dysfunction, Liver Fibrosis, Liver Glycogen, liver metabolism, Longevity, Metabolic, Modeling, mouse model, Mus, Mutant Strains Mice, Natural History, Nitrogen, novel, Pathology, Patient Care, Patients, Phosphorylation, Post-Translational Protein Processing, Prevalence, prevent, Primary carcinoma of the liver cells, Protein-Restricted Diet, Proteins, Regulation, Serum, stable isotope, targeted treatment, Testing, Therapeutic, therapeutic target, Tissues, Transaminases, United States, urea cycle, Urea cycle disorders, Virus, Work | Department of Genetics, BAYLOR COLLEGE OF MEDICINE, Houston, TX 77030, United States |
| 1R01HD103612-01 | Hochedlinger, Konrad | Dissecting mechanistic links between MAPK signaling, genomic hypomethylation and naive pluripotency | R01 | 2021 | Eunice Kennedy Shriver National Institute Of Child Health & Human Development | NICHD | SUMMARY Embryonic stem cells (ESCs) self-renew indefinitely in culture while retaining the capacity to produce all cell types of the body. Mouse ESCs are typically maintained in serum and LIF, which capture a state resembling the normally methylated, post-implantation epiblast, whereas culture of ESC in the presence of inhibitors of MEK1/2 and GSK3, termed ?2i?, captures a hypomethylated, naïve state that resembles the pre-implantation epiblast. As Wnt activation (via GSK3 inhibitor) and MAPK suppression (via MEK1/2 inhibitor) recapitulates the signaling environment of early embryos, 2i-induced hypomethylation offers a tractable and powerful ex vivo system to study the reprogramming of genomic methylation patterns within the pre-implantation embryo. Notably, methylation patterns are not only influenced by external signals but also by sex chromosomes, with female ESCs being hypomethylated compared to male ESCs. The process of female-specific hypomethylation and its connection to the naïve state remain incompletely understood. We recently discovered that suppression of the MAPK pathway through pharmacological inhibition of MEK1/2 or upregulation of the X-linked MAPK phosphatase DUSP9 underlies 2i-induced and female-specific hypomethylation, respectively. Unexpectedly, we found that suppression of the MAPK pathway also compromises genomic stability and the developmental potential of ESCs. Here, we outline 3 complementary aims to dissect the mechanisms by which the MAPK pathway influences DNA methylation in pluripotent cells through either sex chromosomes or external signals. In SPECIFIC AIM 1, we will narrow down the upstream and downstream components of the MAPK pathway responsible for hypomethylation and test candidate targets identified by proteomics approaches. We will further explore the molecular consequences of loss of genomic hypomethylation within the naïve epiblast. In SPECIFIC AIM 2, we will test candidate targets of DUSP9 in female ESCs and integrate results with Aim 1 to define similarities and differences between sex-dependent and environment (2i)-induced hypomethylation. We will further characterize the self- renewal defect we uncovered in ESCs lacking both Dusp9 alleles and assess its dependence on DNA methylation. Lastly, we will determine whether sex-specific methylation differences in ESCs originate from pre- or post-implantation embryos. In SPECIFIC AIM 3, we will investigate whether the mechanistic connection we observed between MAPK signaling and DNA methylation is conserved in naïve human ESCs and whether this information can be exploited to grow more stable human cells. Specifically, we will assess whether the titration of inhibitors that target MAPK signaling or the use of alternative MEK inhibitors increases DNA methylation and decreases genomic instability. Collectively, our work will explore molecular links between MAPK signaling and DNA methylation, genomic stability and developmental potential in pluripotent cells with the goal to dissect basic mechanisms and define improved conditions for human stem cells. | Address, Affect, Alleles, Attenuated, base, blastocyst, BRAF gene, cell type, Cells, Chemicals, Chromosomal Instability, Chromosomal Stability, Cues, Cultured Cells, Data, Defect, Dependence, Development, DNA, DNA Methylation, Embryo, embryonic stem cell, Environment, Epiblast, Epigenetic Process, epigenome, Exhibits, Female, Genes, Genetic Transcription, Genome Stability, genome wide methylation, Genomic Imprinting, Genomic Instability, Genomics, Goals, Human, human embryonic stem cell, human stem cells, Impairment, implantation, imprint, improved, In Vitro, in vivo, induced pluripotent stem cell, inhibitor/antagonist, Karyotype, Knock-out, Lead, LIF gene, Link, Maintenance, male, MAP Kinase Gene, MAP2K1 gene, MAPK phosphatase, Measures, MEKs, Methylation, methylation pattern, Mitogen-Activated Protein Kinase Inhibitor, Mitogen-Activated Protein Kinase Kinases, Molecular, Mus, Mutation Analysis, natural Blastocyst Implantation, Pathway interactions, Pharmacology, Phenotype, phosphoproteomics, Play, pluripotency, Pluripotent Stem Cells, preimplantation, preservation, Process, Proteomics, Protocols documentation, Research Personnel, Role, self renewing cell, self-renewal, Serum, sex, Sex Chromosomes, Sex Differences, Signal Transduction, Somatotype, stem cell model, stem-like cell, System, Testing, Titrations, tool, Up-Regulation, upstream kinase, Work, X Chromosome | MASSACHUSETTS GENERAL HOSPITAL, Boston, MA 02114, United States |
| 1R01GM139894-01 | Merrill, Bradley J | Harnessing multiplexed Cas9 genome editing for sequential genetic manipulations and recording activities in cell lineages | R01 | 2021 | National Institute Of General Medical Sciences | NIGMS | SUMMARY Time is a problem for biologists, especially for those interested in cancer, stem cell, and developmental biology. Whereas cellular processes occur in real time, we most often try to understand biology by piecing together information obtained with static end-point experiments. The goal of this proposal is to expand a novel technology to provide innovative of dealing with problems posed by time in biology. The technology records a ledger of events within the cell?s own genome with CRISPR/Cas9 gene editing tools, which have been developed to execute machine-like instructions in cells. The ledger can be ?read? by next generation DNA sequencing, allowing the reading many ledger entries at one time at once. The presence of multiple ledger entries on a contiguous DNA strand enables all the entries from many cells to be read at the individual cell level. The system of recording is based on combining multiple modular activities in series to develop a cascading process through sequentially activated steps; each step is encoded by a single module. We have developed and validated the essential components of individual modules, and here we propose to build and optimize series of modules linked together in pre-programmed orders. The proposed research is organized by three Specific Aims of 1) expanding the duration of stem cell lineage tracking with a 10-module long cascade, 2) record the history of Wnt signaling in individual cells in a lineage using our technology, and 3) control a ratcheting progression of cellular recording such that cellular events can be identified with a cell division number tracker. Completion of the proposal will provide a substantial new capability for biologists in interrogating the functions of biological systems. | alpha Toxin, Bar Codes, base, beta catenin, Biological Process, biological systems, Biology, cancer stem cell, cell age, Cell Cycle, Cell division, Cell Lineage, Cell physiology, cell type, Cells, Clustered Regularly Interspaced Short Palindromic Repeats, Code, comparative, CRISPR/Cas technology, Dependence, design, Developmental Biology, DNA, DNA biosynthesis, DNA Sequence, DNA sequencing, Elements, Engineering, Event, Excision, experimental study, Exposure to, flexibility, G1 Phase, Genes, genetic manipulation, Genome, genome editing, Goals, Hormones, Individual, innovation, Instruction, interest, Link, Mammalian Cell, Measurement, Mediating, Methods, Names, new technology, next generation, novel, nuclease, Positioning Attribute, prevent, Process, programs, promoter, prototype, Reading, reconstitution, Recording of previous events, Records, repaired, Research, RNA, RNA Sequences, Sampling, Series, Signal Pathway, Signal Transduction, Special Equipment, stem cell biology, stem cells, System, Technology, Time, tool, WNT Signaling Pathway | Department of Biochemistry, UNIVERSITY OF ILLINOIS AT CHICAGO, Chicago, IL 60612, United States |
| 1R01GM139829-01 | Smith, Catharine Lynn | The Positive Roles of Lysine Deacetylase Complexes in Regulating Transcriptional Dynamics | R01 | 2021 | National Institute Of General Medical Sciences | NIGMS | Abstract Whereas traditional models of transcription cast lysine acetyltransferases (KATs, also known as HATs) as tran- scriptional coactivators and lysine deacetylases (KDACs, also known as HDACs) as corepressors, an abun- dance of evidence demonstrates that KDACs can facilitate transcription in a gene-dependent fashion. However, the mechanisms underlying their transcription-promoting functions are poorly understood. The long-term goal of our work is to define mechanisms by which KDACs, KATs, and acetylation regulate signaling-modulated tran- scription. The proposed study utilizes glucocorticoid signaling as a model system. Published studies from the lab demonstrate that KDACs are required not only for glucocorticoid-mediated transcriptional repression but also for transcriptional activation of target genes. Preliminary studies show that KDAC1 is required for GR-activated transcription by multiple mechanisms, depending on the target gene, acting either upstream or downstream of RNA polymerase II recruitment to the transcription start site (TSS). The next logical step is to identify the KDAC1 complexes involved and investigate their roles in glucocorticoid receptor (GR)-activated transcription. The objec- tive of the proposed study is to define the roles of KDACs in the dynamics of the transcriptional cycle at gluco- corticoid receptor (GR)-activated genes. The central hypothesis is that KDAC1-containing complexes act within regulatory elements and/or gene bodies to facilitate efficient transcriptional initiation and elongation at GR-acti- vated genes in a gene-specific fashion. This hypothesis will be tested experimentally through three specific aims. In the first specific aim, the impact of Class I KDACs on the kinetics of transcriptional bursting at GR-activated genes will be measured, working from the hypothesis that their inhibition will decrease the size and/or the fre- quency of bursts at KDAC-sensitive GR target genes. This will be tested using single molecule fluorescent in situ hybridization (smFISH) and live cell imaging of transcription. In the second specific aim, the functional impact of KDAC activity on transcriptional initiation and elongation at GR-activated enhancers and within GR target genes will be defined. Next generation sequencing approaches (ChIP- and nascent transcript-sequencing) will be used to address the hypothesis that Class I KDACs facilitate GR-induced transcriptional initiation or elonga- tion in a gene- and enhancer-specific fashion. In the third specific aim, the identity of the KDAC1-containing complexes that facilitate GR transactivation and their sites of action around GR target genes will be determined. Using biochemical, molecular, and single cell approaches, the working hypothesis that KDAC1 facilitates GR transactivation in the context of the RCOR and/or NuRD complexes active at regulatory elements or within gene bodies will be addressed. This work will generate novel mechanistic knowledge of the transcriptional functions of KDACs that is relevant to basic understanding of cellular processes as well as treatment of disease through modulation of the epigenome. The study is innovative because it will move this new paradigm of KDACs as coactivors beyond traditional static models of transcription by incorporating transcriptional dynamics. | Acetylation, Acetyltransferase, Address, Biochemical, Biological Assay, Biological Models, cancer therapy, Cell physiology, Cells, ChIP-seq, Chromatin, Circadian Rhythms, Clinical, Collaborations, Complex, Coupled, course development, Data, Deacetylase, Development, Disease, Doctor of Philosophy, Drug Targeting, Enhancers, Ensure, Epigenetic Process, epigenome, experience, Fluorescent in Situ Hybridization, Formulation, Frequencies, gene repression, Genes, genetic corepressor, Genetic Transcription, Glucocorticoid Receptor, glucocorticoid-induced orphan receptor, Glucocorticoids, Goals, Histone Deacetylase, Histone H3, Human Pathology, immune function, Impairment, inhibitor/antagonist, innovation, Investigation, Kinetics, Knowledge, Life, Ligands, live cell imaging, Lysine, Maintenance, Measures, Mediating, Metabolism, Methods, Modeling, Molecular, nervous system disorder, next generation sequencing, novel, NuRD complex, Patients, Pharmaceutical Preparations, Physiological Processes, prevent, promoter, Proteins, Public Health, Publishing, recruit, Regulatory Element, Research, Resources, RNA Polymerase II, Role, Signal Transduction, single molecule, Site, Small Interfering RNA, Steroid Receptors, Steroids, Study models, Testing, therapeutic development, Therapeutic Uses, Toxic effect, Transactivation, Transcript, Transcription Coactivator, Transcription Elongation, transcription factor, Transcription Initiation, Transcription Initiation Site, Transcriptional Activation, Transcriptional Regulation, United States National Institutes of Health, Work | Department of Pharmacology, UNIVERSITY OF ARIZONA, Tucson, AZ 85721, United States |
| 1DP1AG069874-01 | Szanton, Sarah L | Reducing racial disparities in AD/ADRD: Addressing structural discrimination and resilience | DP1 | 2020 | National Institute On Aging | NIA | African Americans are more than twice as likely to have Alzheimer?s disease/Alzheimer?s disease related dementias (AD/ADRD) as Whites. This is a preventable gap. The simple yet innovative long-term vision of this LEADR proposal is to erase racial disparities in AD/ADRD burden. In this project, we will 1) develop a measure of structural discrimination and resilience, 2) use it to predict outcomes in AD/ADRD and 3) develop interventions to decrease prevalence and increase resilience. Understanding how to equalize the Black and White AD/ADRD burden will reveal mechanisms that will optimize prevention and care for all. With historical data, innovative approaches, and a commitment to addressing this disparity, we can achieve this objective. The functional impact of AD/ADRD is never due solely to individual decline; it reflects interactions between a person?s decline, their ability to compensate, and the demands of the environment. The resilience to compensate is not just an individual matter, it has many domains including the ability to use remaining intact brain function, coping skills, family support, physical layout of the home, and multiple community and policy factors. Although structural discrimination and resilience are relevant to AD/ADRD and function, there are currently no measurement instruments. We will use the sequential exploratory mixed methods Instrument Design Model in which researchers incorporate key stakeholders into the instrument design process. This instrument will measure eight dimensions of structural discrimination and resilience plus family support, greenspace, and social connection. Zip codes across the lifespan will be used to merge historical data to measure multiple risk or protective factors such as school district funding, environmental toxins, and amount of accessible greenspace. We will construct the instrument with older adults and researchers, cognitively test, pilot test, refine and then field the instrument in national datasets supported by the NIH. The intervention development stage will include: 1) insights from the previous qualitative portions; 2) results of the data collection phase; 3) insights from a larger stakeholder groups of policy makers, researchers, advocates, people living with AD/ADRD and their families to review findings and identify potential intervention mechanisms. This program of work will move beyond individual and family interventions to address the structural determinants of AD/ADRD. Developing a reliable, valid measure of structural racial discrimination, being able to test its role in AD/ADRD, and then to use it as a framework for developing population-level interventions, is a high-risk, high-reward goal - worthy of the NIH investment in AD/ADRD. A significant side benefit is that because many other conditions related to structural discrimination are also on the causal pathway to AD/ADRD, this effort will also enhance our understanding of hypertension, stroke, heart disease, and other inflammatory diseases. The project uses the distinct strengths of the applicant, the outstanding research environment, and existing NIA resources to work towards solving crucial disparities that tax families and society. | Address, Advocate, African American, Alzheimer's Disease, Alzheimer's disease related dementia, Brain, Caring, Code, cognitive testing, Communities, Coping Skills, Data, Data Collection, Data Set, design, Dimensions, Discrimination, Disease, Elderly, Environment, Family, family support, Funding, Goals, Green space, Heart Diseases, high reward, high risk, Home environment, Hypertension, Individual, Inflammatory, innovation, insight, instrument, Intervention, Investments, Longevity, Measurement, Measures, Methods, model design, outcome prediction, Pathway interactions, Persons, Phase, Policies, Policy Maker, Population, Prevalence, Prevention, Process, programs, protective factors, racial discrimination, racial disparity, Research, Research Personnel, resilience, Resources, Risk Factors, Role, school district, Side, social, Societies, Stroke, Structure, Taxes, Testing, therapy development, Toxic Environmental Substances, United States National Institutes of Health, Vision, Work | JOHNS HOPKINS UNIVERSITY, Baltimore, MD 21218, United States |
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