R01AI156186

Deciphering the Role of Noncoding Variation in the Pathogenesis of Multiple Sclerosis - 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 the 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. 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) 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, which 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 both the genetic and cellular mechanisms governing TH17 cell pathogenicity in MS and discover new loci with unknown functions in disease etiology.

Duke University

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Durham, North Carolina 277100004 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 394% from $623,436 to $3,077,928.