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Translating Genetic Risk Factors to Therapies: From Big Data to Druggable Targets

将遗传风险因素转化为治疗方法：从大数据到可药物靶点

基本信息

批准号：
10668535
负责人：
Benjamin C. Shaw
金额：
$ 8.45万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10668535
关键词：
Address Affect Alternative Splicing Alzheimer&apos s Disease Alzheimer&apos s disease risk American Amyloid Amyloid beta-Protein Animal Model Antigen-Antibody Complex Award Big Data Biological Assay Brain CRISPR/Cas technology Caring Cell Culture Techniques Cell Line Cell Surface Receptors Cell surface Cells Cellular biology Clinical Clinical Trials Co-Immunoprecipitations Communication Complex Confocal Microscopy Data Data Analyses Development Disease Dose Drug Targeting Educational workshop Electronic Health Record Engineering Enzyme-Linked Immunosorbent Assay Etiology Exons Faculty Functional disorder Future Gene Chips Gene Expression Genetic Genetic Techniques Goals Heritability Human Human Subject Research Immune Immunoassay Impairment In Situ In Vitro Individual Institution Knowledge Learning Ligand Binding Domain Manuscripts Measures Mentors Mentorship Microglia Microscopy Modeling Molecular Biology Molecular Genetics Molecular and Cellular Biology Multiple Sclerosis Myelogenous Neurodegenerative Disorders Neurosciences Oral PTPN6 gene Pathology Patients Peptides Phagocytosis Phase Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Pluripotent Stem Cells Positioning Attribute Postdoctoral Fellow Protein Isoforms Proteins Proto-Oncogene Proteins c-akt Quality of life RNA Splicing Refractory Disease Research Research Personnel Resolution Risk Factors Role Sampling Scientist Signal Transduction Single Nucleotide Polymorphism Small Interfering RNA Societies System TREM2 gene Technical Expertise Techniques Technology Therapeutic Time Tissue Sample Training Transfection Translating Tyrosine Variant Viral Western Blotting Work Writing abeta toxicity autosome brain cell career confocal imaging data mining druggable target effective therapy experience experimental study gain of function genetic risk factor genetic variant genome editing genome wide association study glial activation graduate school graduate student human data human disease human subject human tissue hyperphosphorylated tau immunoregulation improved induced pluripotent stem cell inhibitor insight meetings monocyte mouse model multiple sclerosis treatment nano-string neuroimmunologic disease neurotoxicity new therapeutic target next generation novel overexpression pharmacologic post-doctoral training receptor research clinical testing sample collection single cell sequencing single-cell RNA sequencing skills symposium tau Proteins tenure track therapeutic target undergraduate student

项目摘要

PROJECT SUMMARY Genome-wide association studies (GWAS) provide insight to underlying etiologies of disease not obvious through clinical evaluation or pathophysiology alone. Genetic variants associated with complex, often refractory diseases such as Alzheimer’s Disease (AD) and Multiple Sclerosis (MS) may hold the key for the next generation of treatment options. Leveraging genetic data with current standards of care and known pathophysiology can provide a strong premise for mechanistic studies and novel drug targets. My current work studies the molecular genetics of CD33 in AD under Dr. Steve Estus. CD33 normally acts to inhibit microglial activation in the brain, suppressing amyloid clearance. We are investigating how the AD-protective single nucleotide polymorphism (SNP) in CD33 modulates protein, and thereby cellular, function. This SNP leads to an increase in an alternative CD33 protein isoform which, based on our recent genetic data, may promote—rather than suppress—microglial activation. I will learn new technical skills during the F99 phase of this award, and I will use these skills as I switch focus to MS and progress into the K00 phase to acquire additional, powerful techniques and models including work with patient samples, pluripotent stem cells, single-cell sequencing technologies, and animal models. In Specific Aim 1, I detail how my training in molecular biology and genetic concepts has allowed me to conceive independent hypotheses and carry out complex experiments. My doctoral work on the molecular genetics of CD33 and its association with reduced AD risk has provided training in GWAS interpretation, quantitative PCR, immunoassays such as Western blotting and co-immunoprecipitation, and genetic techniques including transfection and genome editing strategies in cell culture. In Specific Aim 2, I will continue to develop as a scientist and finish my doctoral work, carrying out increasingly complex studies to include high-resolution confocal imaging and subcellular localization, measuring time- and dose-dependent protein phosphorylation in situ, gene expression arrays, and functional assays including phagocytosis in vitro. I will also continue developing my professional skills such as oral and written communication, networking, and mentorship. In Specific Aim 3, I will extend my doctoral training to include work with human tissue samples and mouse models of MS. I have not yet identified a specific postdoctoral mentor, but my ideal mentor will have experience conducting human subjects research, using mouse models of MS, and have a strong track record of training fellows to become tenure-track faculty. I will identify a mentorship team to guide my technical and professional development during this phase. I will leverage my current training in molecular genetics to identify MS-associated functional SNPs, my training-in-progress to identify the mechanism behind these SNPs at the protein and intracellular signaling levels, and my future training with murine models and human subjects to establish a high- impact, translational career, combining genetic, clinical, and pathology findings for pharmacological breakthroughs in neuroimmune diseases.

项目总结