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Deciphering the role of noncoding variation in the pathogenesis of multiple sclerosis

解读非编码变异在多发性硬化症发病机制中的作用

基本信息

批准号：
10450807
负责人：
Maria Ciofani
金额：
$ 61.86万
依托单位：
DUKE UNIVERSITY
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：
2021-07-15 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10450807
关键词：
Antigens Autoimmunity Automobile Driving Binding Bioinformatics Biological Assay Brain CD4 Positive T Lymphocytes CRISPR/Cas technology Cell physiology Cells Cerebrospinal Fluid Chromatin Chromatin Loop Chronic Clinic Clinical Core Facility Data Demyelinations Development Disease Disease susceptibility Elements Enhancers Environmental Risk Factor Epigenetic Process Etiology Experimental Autoimmune Encephalomyelitis Explosion Functional disorder Gene Expression Profile Gene Expression Regulation Gene Targeting Genes Genetic Genetic Variation Genome Genomic approach Genomics Genotype Glean Goals Human Immune system Immunologist In Vitro Inflammatory Institutes Knowledge Link Machine Learning Maps Mediating Methods Modeling Molecular Molecular Conformation Multiple Sclerosis Mus Myelin Neuraxis Neurology Nucleic Acid Regulatory Sequences Pathogenesis Pathogenicity Patients Phenotype Physiological Physiology Regulator Genes Regulatory Element Reporter Research Personnel Risk Role Sampling Scientist Specialist Spinal Cord T cell response T-Lymphocyte T-Lymphocyte Subsets Technology Th1 Cells Therapeutic Intervention Transcriptional Regulation Untranslated RNA Variant Work analytical method base causal variant disorder risk epigenome editing experimental study gene therapy genetic variant genome wide association study in vivo insight machine learning prediction mouse model multiple omics multiple sclerosis patient neuroimmunology neuroinflammation novel promoter risk variant stem transcription factor

项目摘要

Project Summary Multiple sclerosis (MS) is a chronic, inflammatory condition of the brain and spinal cord mediated largely by pathogenic T cell responses to myelin antigens, resulting in demyelination of the central nervous system (CNS). Myelin-reactive T cells are also crucial for induction of the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Studies of MS and EAE implicate CD4 T helper (Th) cells in disease pathogenesis, including pro-inflammatory Th17 and Th1 cells. In this regard, the disease-promoting ability of these T cell subsets stems from both their capacity to target and infiltrate the CNS and their pro-inflammatory effector function. An interplay between genetic and environmental factors is implicated in the pathogenesis of MS. However, despite a wealth of genome wide association data (GWAS) data revealing a strong genetic contribution to MS, it has been challenging to identify the bona fide disease-promoting gene target(s) of many risk-associated variants, and the cellular compartment in which they contribute to dysregulation. In preliminary work, we have applied global genomics approaches to map MS-associated noncoding risk variants to their long-range target gene by physically capturing enhancer-promoter interactions. These MS-implicated genes were further prioritized based on dysregulated expression signatures in pathogenic Th17 cells derived from MS patients. Using this approach, we have identified putative regulatory MS variants and gene targets that control CD4 T cell function in MS that are the basis of this application. We hypothesize that identifying noncoding variants that alter the regulatory function of cis elements controlling proinflammatory T cells will provide novel mechanistic insights into the underlying etiology governing the development of MS. Here, we propose an integrative strategy to prioritize and validate causal genetic variants in MS pathogenesis. The goal of Aim 1 is to determine the contribution of noncoding risk variants to CD4 T cell gene regulation. In particular, we will employ a combination of high-throughput regulatory reporter assays and machine learning approaches to identify SNPs with regulatory function in primary human CD4 T cells. In Aim 2, we will determine the mechanism by which these regulatory variants contribute to altered T cell function and pathogenicity in MS. Complementary CRISPR/Cas9-mediated genetic and epigenetic perturbations will define the enhancer context of risk alleles and delineate bona fide regulatory gene targets of regulatory risk variants. Moving from genotype to phenotype, we will define true causal variants that contribute to disease etiology in the context of an intact immune system using genetic interventions that model conserved risk variants in mice. Together, the proposed experiments will advance our understanding of the both the genetic and cellular mechanisms governing Th17 cell pathogenicity in MS and discover new loci with unknown functions in disease etiology.

项目总结