R01AI167416

Epigenetics of the Autoantibody Response in Systemic Lupus - Project Summary/Abstract

Epigenetics of the Autoantibody Response in Systemic Lupus. Like "mature" antibody responses to viruses and bacteria, the lupus autoantibody response requires B cell class-switch DNA recombination (CSR), somatic hypermutation (SHM), and plasma cell differentiation. As we have shown, epigenetic factors, including histone modifiers (such as SIRT1) and inhibitors (such as butyrate), modulate B cell expression of AID (gene: AICDA/AICDA) and BLIMP-1 (PRDM1/PRDM1), which are critical for CSR/SHM and plasma cell differentiation, respectively.

Towards a better definition of the epigenetic landscape of lupus B cells, we hypothesize that TET2, a key epigenetic factor, mediates the lupus autoantibody response, as prompted by the B cell-intrinsic role of TET2 in CSR/SHM and plasma cell differentiation (our recent findings). We argue that TET2 is induced by the stimuli that induce B cell CSR/SHM and plasma cell differentiation, and it is upregulated in lupus B cells. We also argue that TET2 boosts transcription of AICDA and PRDM1 through its Fe2+ and α-ketoglutarate (α-KG)-dependent catalytic activity for DNA demethylation, as well as its non-catalytic function, i.e., recruiting OGT (encoded by X-linked OGT/OGT) to these loci to effect histone glycosylation. Finally, we contend that B cell TET2 transduces hormonal, nutritional, and metabolic cues into epigenetic changes to modulate autoantibody responses, as TET2 transcription could be upregulated by estrogen (E2, our preliminary data) and vitamin A, and TET2 is activated by vitamin C, but inhibited by fumarate (a metabolite and α-KG competitor) – as shown by us, E2 boosts AID expression, which would enhance females' antibody and autoantibody responses.

With extensive experience in and commitment to the mechanistic understanding of human and mouse lupus autoantibody responses, we are uniquely poised to test our hypotheses using molecular B cell biology systems, cutting-edge epigenetic tools (hydroxymethyl DNA analysis, bisulfite and oxidative bisulfite conversion, ChIP and ATAC-seq), genetically modified mice (TgAicda-CreTet2fl/fl, Tet2HxD-Mut/HxD-Mut and Tet2OGT-Mut/OGT-Mut knockin mice, TgAicda-CreOGTfl/fl, Tet2HxD-Mut/HxD-MutTgAicda-CreOGTfl/fl, MRL/lpr TgAicda-CreTet2fl/fl, MRL/lpr Tet2HxD-Mut/HxD-Mut and MRL/lpr TgAicda-CreOGTfl/fl), proprietary humanized H-Mice® and lupus-H-Mice® models.

Aim 1 addresses human and mouse B cell differentiation stage-specific (resting, activated, plasma, and memory cell) regulation of TET2, TET2 protein stability, E2 upregulation of TET2 transcripts, and underlying mechanisms.

Aim 2 addresses the B cell-intrinsic role of TET2 in promoting AID and BLIMP-1 expression, the underlying mechanisms (active DNA demethylation and OGT-mediated histone glycosylation), and the potentiation effect of TET2 inducer vitamin A and activator vitamin C, and suppressive effect of TET2 catalytic inhibitor (fumarate, TET-IN-C35 or BOBCAT339) alone or combined with OGT ablation or Tet2OGT-Mut/OGT-Mut knockin.

Aim 3 analyzes dysregulation of TET2 and TET2-mediated epigenetic mechanisms in human and mouse lupus B cells, addresses the role of TET2 in lupus, and explores TET2 inhibitors and OGT inhibitor ST045849 as lupus therapeutics.

Our experiments will unveil novel and targetable epigenetic mechanisms that integrate environmental cues to inform the lupus autoantibody response.

The University Of Texas Health Science Center At San Antonio

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]

San Antonio, Texas 782293901 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 388% from $733,336 to $3,576,652.