Chris Audu
Assistant Professor of Vascular Surgery
Adjunct Assistant Professor of Medicinal Chemistry
Vascular Surgery, Medicinal Chemistry, Chromatin Modifying enzymes, Epigenetics, Aneurysms
Biological Chemistry Program
Education
Research
Abdominal aortic aneurysms (AAA) are an asymptomatic vascular disease with a mortality rate greater than 80% in patients who rupture. Recent studies estimate that about one million people in the US live with AAA. Diagnosis is usually incidental, given its clinically silent nature, and can be associated with congenital connective tissue disorders. The mainstay of therapy remains open or endovascular surgical intervention. Pharmacologic interventions to slow AAA growth, and biomarkers to aid in diagnostic and/or prognostic evaluation of AAA rupture risk, are a highly desired and critical clinical need. The scientific challenges to meeting this need can be broadly grouped into three categories: insufficient mechanistic understanding of AAA developmental biology, inadequate human AAA disease models, and a dearth of medicinal chemistry efforts towards AAA therapeutic discovery.
A key molecular mechanism in AAA development is endothelial to mesenchymal transition (EndMT). Propelled by dysregulated TGF-b cytokine signaling, EndMT causes vascular endothelial cells (EC) lining the intima layer of blood vessels and maintaining vessel wall barriers to transition to mesenchymal-like stem cells (MSC). These MSCs lack adhesion molecules and tight junctions, are more permeable to invading cells, and exhibit phenotype plasticity – becoming impaired angiogenic cells, fibroblasts, osteocytes, or smooth muscle cells – depending on environmental cues. Highly regulated EndMT, and the interaction of ECs with macrophages and vascular smooth muscle cells is necessary for normal vascular remodeling in areas of high shear stress and following injury.
Our laboratory has projects designed to test the central hypothesis that identifying and targeting key chromatin modifying enzymes (CME) involved in EndMT-induced AAA development will provide mechanistic, biomarker and therapeutic advances against this lethal disease. This hypothesis will be tested using complementary, multidisciplinary projects that are structured to lend insight into AAA early development (Project A), mechanistic insight into AAA progression mediated by EndMT (Project B) and therapeutic insight by studying and targeting SETDB2 – a CME involved in AAA (Project C).
References
- Audu CO, Wolf SJ, Joshi AD, Moon JY, Melvin WJ, Sharma SB, Davis FM, Obi AT, Wasikowski R, Tsoi LC, Barrett EC, Mangum KD, Bauer TM, Kunkel SL, Moore BB, Gallagher KA. Histone demethylase JARID1C/KDM5C regulates Th17 cells by increasing IL-6 expression in diabetic plasmacytoid dendritic cells. JCI Insight. 2024 Jun 24;9(12):e172959. PMID: 38912581
- Audu CO, Melvin WJ, Joshi AD, Wolf SJ, Moon JY, Davis FM, Barrett EC, Mangum KD, Deng H, Xing X, Wasikowski R, Tsoi LC, Sharma SB, Bauer TM, Shadiow J, Corriere MA, Obi AT, Kunkel SL, Levi B, Moore BB, Gudjonsson JE, Smith AM, Gallagher KA. Macrophage-specific inhibition of the histone demethylase JMJD3 decreases STING and pathologic inflammation in diabetic wound repair. Cell Mol Immunol. 2022 Nov;19(11):1251-1262. PMID: 36127466
- Huang H, McGrath A, Audu CO, Cernak, T. Catalyst: Systems chemistry links reactions to molecular function. Chem. 2024, 10(8):2333 https://doi.org/10.1016/j.chempr.2024.06.009
- McGrath A, Huang H, Brazeau J-F, Zhang Z, Audu CO, Vellore NA, Lu Z, Shi Z, Venable JD, Gelin CF, Cernak T., Modulating the potency
of BRD4 PROTACs at the systems level with amine-acid coupling reactions J Med Chem. 2024, doi: 10.1021/acs.jmedchem.4c02047. PMID: 39688565