THE AUDU LAB
The Audu Lab at the University of Utah sits at the intersection of several investigative fields in a quest to develop novel therapeutics targeting vascular disease. We employ techniques of biophysics, immunology, bioinformatics and medicinal chemistry to explore the role of chromatin modifying enzymes (many of which there is no structural information) in vascular pathophysiology. Our projects explore the structure and function of these proteins with the eventual goal of high throughput experimentation (HTE) applied in direct-to-biology (D2B) analyses.
RESEARCH
The Audu lab investigates the epigenetic mechanisms underlying vascular complications in diabetes, focusing on chromatin-modifying enzymes and their role in inflammation, endothelial dysfunction, and impaired wound healing. One area of study centers on SETDB2, a histone methyltransferase that regulates macrophage-mediated inflammation and lipid metabolism. The lab applies structural analysis and NanoSAR technology to develop targeted modulators of SETDB2. Another key focus is on sirtuins (SIRT1, 3, and 6), NAD+-dependent histone deacetylases implicated in diabetic vascular disease. The team explores how sirtuin depletion influences macrophage-endothelial interactions, leading to endothelial-to-mesenchymal transition (EndMT) and vascular dysfunction. Using immunologic and medicinal chemistry approaches, the lab aims to develop tissue-specific modulators to mitigate these pathologic effects.
IMMUNOLOGY
Sirtuins’ Role in Diabetic Macrophage Induced Endothelial to Mesenchymal Transition
Diabetes affects approximately 12% of the US population (39 million people), exerting a significant cost on the healthcare system. Its systemic effects on vascular biology (such as persistent inflammation, arterial stiffening, venous thromboembolism, arteriosclerosis, and impaired wound healing), is responsible for significant morbidity and mortality. Mechanistically, diabetes causes these pathologic effects, in part, by altering macrophage and endothelial cell activity, phenotype and function in an epigenetic manner.
One group of epigenetic enzymes implicated in diabetes are the sirtuins (SIRT), a class of NAD+-dependent histone deacetylases. Activation of sirtuins remove acetyl marks off histone proteins, reducing DNA unspooling which generally leads to decreased gene transcription. In so doing, sirtuins regulate gene transcription and translation. There are seven structurally unique sirtuin classes, of which SIRT1, 3 and 6 are the best studied in diabetes where they are relatively depleted due to decreased production of NAD+. This reduction of SIRT1, 3 and 6 in diabetes has been shown to increase transcription of pro-inflammatory genes in cardiac, hepatic, renal and pulmonary tissue. Importantly, SIRT1,3 and 6 dysfunction has not been studied in the setting of bone marrow monocytes/macrophage interactions with vascular endothelial cells. Therefore, we hypothesize that epigenetic alterations by Sirtuins 1, 3 and 6 play a significant role in diabetic macrophage – endothelial cell cross talk that results in pathologic endothelial-to-mesenchymal transition (EndMT). EndMT is implicated in a host of vascular changes in diabetes including arterial stiffening, venous thromboembolism, and impaired wound healing.
Our laboratory will utilize immunologic, physiologic and phenotypic techniques to understand how sirtuins modulate vascular endothelial cells and promote mesenchymal transition that leads to vascular impairment. Simultaneously, we will embark on medicinal chemistry techniques to develop modulators for sirtuins that are tissue specific. We believe understanding this critical pathway will pave the way for biochemical assay design, biomarker development, therapeutic advance, and creative synthetic discovery.
MEDICINAL CHEMISTRY
The Rational Design of SETDB2 Modulators
One Chromatin Modifying Enzyme (CME) known for its role in cardiovascular disease is the SET Domain Bifurcated Histone Methyltransferase 2 (SETDB2). SETDB2 is a histone methyltransferase responsible for methylating lysine-9 on histone 3 (H3K9me3) – a repressive marker on gene promoters that prevents cytokine gene transcription. SETDB2 has been shown to play a significant role in regulating macrophage-mediated inflammation, lipid metabolism, and fibroblast production in vascular disease. For instance, in the pathologic diabetic state, decreased SETDB2 expression results in continuous macrophage-mediated inflammatory cytokine production and impaired wound healing. On the other hand, in aortic aneurysmal disease, SETDB2 potentiates inflammation by increasing macrophage and smooth muscle cell metalloproteinase activity that ultimately leads to aortic wall degeneration and rupture. Thus, SETDB2 plays a significant role in vascular diseases that affect a significant portion of the population, and for which there are limited medicinal therapeutic options.
Our laboratory is involved in structural determination of SETDB2 and applying our findings to rational design of modulators using NanoSAR (nanoscale synthesis and affinity ranking) technology
CLINICAL TRIALS
Stay tuned for more updates on clinical trials.
PRINCIPAL INVESTIGATOR
Chris Audu, MD, PhD, immigrated from Nigeria to attend university at Purdue - Indianapolis, where he got his BSc in Chemistry and was an inaugural undergraduate researcher in the Distributed Drug Discovery program started by Drs. Martin O'Donnell and William Scott. From here, he pursued his passion for medicine and chemistry by obtaining MD and PhD degrees at Dartmouth. He obtained his PhD in 2013 with Prof. Dale Mierke generating and validating protein models for high throughput, small molecule screening of difficult proteins - such as GPCRs and viral capsids. Following his MD graduation in 2016, he started his surgical training at Dartmouth and eventually moved to the University of Michigan to complete training in Vascular Surgery in the integrated residency pathway. During residency, he completed postdoctoral work in the labs of Drs. Katherine Gallagher (Immunology) and Timothy Cernak (Medicinal Chemistry), to develop novel ideas on high throughput experimentation in organic synthesis, and the epigenetic immunology of diabetic wound healing, aortic aneurysm development, and venous thromboembolism.
He joined the University of Utah Department of Surgery Fall 2024 as an Assistant Professor of Vascular Surgery, and is also an Adjunct Assistant Professor of Medicinal Chemistry. He, along with his team, look forward to making seminal discoveries for therapeutic benefit in vascular pathophysiologies.
TEAM
Working with Christopher Audu, MD, PhD, are scientist, Larisse Pontes, and senior lab specialist, Ramandeep Kaur.
HIGHLIGHTED PUBLICATIONS
Modulating the Potency of BRD4 PROTACs at the Systems Level with Amine-Acid Coupling Reactions.
McGrath A, Huang H, Brazeau JF, Zhang Z, Audu CO, Vellore NA, Zhu L, Shi Z, Venable JD, Gelin CF, Cernak T.
J Med Chem. 2025 Jan 9;68(1):405-420. doi: 10.1021/acs.jmedchem.4c02047. Epub 2024 Dec 17.
PMID: 39688565
The STAT3/SETDB2 axis dictates NF-κB-mediated inflammation in macrophages during wound repair.
Mangum KD, denDekker A, Li Q, Tsoi LC, Joshi AD, Melvin WJ, Wolf SJ, Moon JY, Audu CO, Shadiow J, Obi AT, Wasikowski R, Barrett EC, Bauer TM, Boyer K, Ahmed Z, Davis FM, Gudjonsson J, Gallagher KA.
JCI Insight. 2024 Oct 22;9(20):e179017. doi: 10.1172/jci.insight.179017.
PMID: 39435663
Free PMC article.
Audu CO, Schechtman DW, Davis FM.
Clin Colon Rectal Surg. 2023 Dec 15;37(6):417-423. doi: 10.1055/s-0043-1777667. eCollection 2024 Nov.
PMID: 39399138
Free PMC article.
Review.
Melvin WJ, Bauer TM, Mangum KD, Audu CO, Shadiow J, Barrett EC, Joshi AD, Moon JY, Bogle R, Mazumder P, Wolf SJ, Kunke SL, Gudjonsson JE, Davis FM, Gallagher KA.
JCI Insight. 2024 Aug 27;9(19):e179012. doi: 10.1172/jci.insight.179012.
PMID: 39250432
Free PMC article.
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.
JCI Insight. 2024 Jun 24;9(12):e172959. doi: 10.1172/jci.insight.172959.
PMID: 38912581
Free PMC article.
Diabetic Wound Keratinocytes Induce Macrophage JMJD3-Mediated Nlrp3 Expression via IL-1R Signaling.
Wolf SJ, Audu CO, Moon JY, Joshi AD, Melvin WJ, Barrett EC, Mangum K, de Jimenez GS, Rocco S, Buckley S, Ahmed Z, Wasikowski R, Kahlenberg JM, Tsoi LC, Gudjonsson JE, Gallagher KA.
Diabetes. 2024 Sep 1;73(9):1462-1472. doi: 10.2337/db23-0968.
PMID: 38869447
Free PMC article.
Incivility, Work Withdrawal, and Organizational Commitment Among US Surgeons.
Santosa KB, Kayward L, Matusko N, Jagsi R, Audu CO, Kwakye G, Waljee JF, Sandhu G.
Ann Surg. 2023 Mar 1;277(3):416-422. doi: 10.1097/SLA.0000000000005186. Epub 2021 Aug 20.
PMID: 36745764
Sharma SB, Melvin WJ, Audu CO, Bame M, Rhoads N, Wu W, Kanthi Y, Knight JS, Adili R, Holinstat MA, Wakefield TW, Henke PK, Moore BB, Gallagher KA, Obi AT.
Blood. 2023 Feb 16;141(7):725-742. doi: 10.1182/blood.2022015917.
PMID: 36493338
Free PMC article.
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.
Cell Mol Immunol. 2022 Nov;19(11):1251-1262. doi: 10.1038/s41423-022-00919-5. Epub 2022 Sep 20.
PMID: 36127466
Free PMC article.
IFN-κ is critical for normal wound repair and is decreased in diabetic wounds.
Wolf SJ, Audu CO, Joshi A, denDekker A, Melvin WJ, Davis FM, Xing X, Wasikowski R, Tsoi LC, Kunkel SL, Gudjonsson JE, O'Riordan MX, Kahlenberg JM, Gallagher KA.
JCI Insight. 2022 May 9;7(9):e152765. doi: 10.1172/jci.insight.152765.
PMID: 35358091
Free PMC article
de Almeida Feitosa MS, de Almeida AJPO, Dantas SH, de Lourdes Assunção Araújo de Azevedo F, de Souza Júnior JF, Gonçalves TAF, de Lima Silva S, Soares EMC, Alves HF, Lima TT, da Silva Pontes LV, Guerra RR, Araújo IGA, de Medeiros IA. Carvacrol prevents D-( +)-galactose-induced aging-associated erectile dysfunction by improving endothelial dysfunction and oxidative stress in rats. Naunyn Schmiedebergs Arch Pharmacol. 2024 Dec;397(12):10061-10073. doi: 10.1007/s00210-024-03264-8. Epub 2024 Jul 5. PMID: 38967826.
de Almeida AJPO, de Oliveira JCPL, da Silva Pontes LV, de Souza Júnior JF, Gonçalves TAF, Dantas SH, de Almeida Feitosa MS, Silva AO, de Medeiros IA. ROS: Basic Concepts, Sources, Cellular Signaling, and its Implications in Aging Pathways. Oxid Med Cell Longev. 2022 Oct 19;2022:1225578. doi: 10.1155/2022/1225578. PMID: 36312897; PMCID: PMC9605829.
da Câmara Rocha J, da Franca Rodrigues KA, do Nascimento Néris PL, da Silva LV, Almeida FS, Lima VS, Peixoto RF, da Câmara Rocha J, de Azevedo FLAA, Veras RC, de Medeiros IA, da Silva WAV, Lima-Junior CG, de Almeida Vasconcellos MLA, do Amaral IPG, de Oliveira MR, de Souza Lima Keesen T. Biological activity of Morita-Baylis-Hillman adduct homodimers in L. infantum and L. amazonensis: anti-Leishmania activity and cytotoxicity. Parasitol Res. 2019 Oct;118(10):3067-3076. doi: 10.1007/s00436-019-06403-w. Epub 2019 Aug 7. PMID: 31392413.
Explore more research conducted by the Vascular Surgery Department.
NEWS
Stay tuned!
CONTACT US
MAILING ADDRESS
Chris Audu, TVP laboratory
Veteran Affairs Medical Center, Building 2, Room 2C43
500 Foothill Drive
Salt Lake City, UT 84148