Brian Smith

Credentials: PhD

Position title: Associate Professor of Biochemistry

Email: brismith@mcw.edu

Bromodomains are epigenetic “readers” of lysine acetylation on histones and transcription factors; bromodomain binding to acetylated histones/proteins regulates transcription in a cell-type dependent manner. Early treatment of non-obese diabetic (NOD) mice with an inhibitor of the bromodomain and extraterminal (BET) family (Brd2-4) was recently shown to suppress the development of autoimmune diabetes. The protective effects of BET inhibition correlated with anti-inflammatory and pro-proliferative phenotypes in macrophages and β-cells, respectively; however, the mechanisms are poorly understood. We hypothesize that BRD4 regulates β-cell proliferation and macrophage inflammation in islets and that inhibition of BRD2 and BRD3 are liabilities of pan-BET inhibitors in autoimmune diseases. Consistent with this hypothesis, pan-BET inhibition is associated with impaired learning and memory and reduced immune system function. We are examining BRD4 inhibition as a therapeutic strategy in autoimmune diabetes. We determined that BRD4 inhibition prevents macrophage activation and production of inflammatory mediators known to damage β-cells and protects β-cells from cytokine-mediated damage. We are also exploiting our expertise in chemical biology to target BRD4 inhibitors to macrophages and β-cells selectively. Our long-term goals are to elucidate the cell-type-specific mechanisms of transcriptional regulation by BET bromodomains and develop novel selective BET inhibitors to halt the development and progression of autoimmune diabetes.