R01AI156724

Disease and Race Specific Single-Cell Epigenetic Mechanisms in Human SLE - Project Summary

Systemic Lupus Erythematosus (SLE) is a prototypic autoimmune disease characterized by dysregulated interferon responses and loss of self-tolerance to cellular antigens that result in inflammatory processes. These processes ultimately lead to systemic end-organ damage. There are striking genetic and clinical differences between European American (EA) and African American (AA) SLE patients, resulting in disparities in their diagnoses, management, and outcomes. Despite decades of research and over 100 risk loci identified, the underlying mechanisms driving the pathogenesis of SLE and its racial disparities remain incompletely understood.

Our lab has joined forces with the team led by Jason Buenrostro, PhD, at Harvard to evaluate and understand how epigenetic regulation in specific cell types contributes to both disease- and race-specific SLE pathogenesis. We use a SCI-ATAC-seq (Single Cell Indexing Assay for Transposase-Accessible Chromatin) method, developed and optimized in the Buenrostro Laboratory, to assess disease- and race-specific differences in genome-wide chromatin accessibility (CA) in cell subtypes from cryopreserved peripheral blood mononuclear cells.

Integrating these data with genotyping data allows us to identify allelically imbalanced variants that are enriched in regions of CA (CAQTLS), suggesting a mechanistic role for these variants in regulating CA. Our preliminary data conducted in EA SLE and healthy controls demonstrate that we are able to define multiple major PBMC cell subsets and that extensive differential CA and CAQTLS discriminate between SLE case and control subjects.

We now propose an expanded study that will not only evaluate disease-specific CA and CAQTL alterations in a much larger sample but also race-specific alterations. Integrating single-cell transcriptomic data and clinical data with CA and CAQTL data will facilitate the functional interpretation of SLE-relevant CA differences.

Our goals for this AR077434 resubmission are to:

1) Define cell type-specific differences in chromatin accessibility that identify both disease-specific and race-specific alterations.
2) Identify cell type and race-specific CAQTLS that associate with differences in CA between SLE cases and controls.
3) Define the mechanistic relationships between CA, CAQTLS, gene expression architectures, within the context of cis co-accessibility networks.

We believe this project positions us at the leading edge to develop a precise epigenetic roadmap connecting genetic variation to deleterious cellular and clinical phenotypes that underlie the disease-specific mechanisms of SLE and its remarkable race-specific disparities.

Oklahoma Medical Research Foundation

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]

Oklahoma City, Oklahoma 731045005 United States

Single Zip Code

Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-19-056)

Amendment Since initial award the total obligations have increased 385% from $850,595 to $4,125,381.