Friday, November 22, 2024
11/22/2024
Systemic lupus erythematosus (SLE) persists as a chronic inflammatory autoimmune disease and is characterized by the production of autoantibodies and immune complexes that affects multiple organs. The underlying mechanism that triggers and sustain disease are complex and involves certain susceptibility genes and environmental factors. Plasma cells (PCs) are derived from B cells and are responsible for the production of protective antibodies against infectious agents, but they also produce pathogenic antibodies in autoimmune diseases, as in SLE. NZB/W F1 female mice and BXSB/Yaa male mice spontaneously develop autoimmunity that closely resembles human SLE. What induces a PC cell to become a normal versus an autoimmune antibody secreting PC is not well understood, but there are several transcription factors that are both supportive and repressive of B cell to PC differentiation. The goal of these studies is to define how selective histone deacetylase inhibition alters the development of pathogenic B cells to PC in SLE. The long-term goals of this proposal are to determine how acetylation status of specific proteins modulates the development of B cells to PC and to target autoreactive PC development pharmacologically. If we can identify the signals that modulate aberrant PC lineage programming, we hope to intervene to block the development of these autoreactive PC and correct the pathogenic production of autoantibodies in SLE. We hypothesize that B cells in lupus mice can be reprogrammed through acetylation of specific proteins to prevent PC autoantibody production. To test our hypothesis we will use both in vivo and vitro lupus animal models. By linking in vitro and in vivo lupus mouse studies, we will define a comprehensive picture of the mechanism(s) by which HDAC6 inhibitors alters B cell function. Dysregulation of acetylation has been implicated in various human diseases, including viral infections, inflammation, neurodegenerative diseases, metabolic disorders, and cancer. The role of HDAC6 has been shown to modulate many disease pathways. With the use selective HDAC6 inhibitors already in clinical trials for other diseases, and depending on the results, the studies can be quickly translated to a clinical setting for SLE.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
