Abhinav Diwan, MD, FACC, FAHA

Professor
Internal Medicine
Cardiovascular Medicine
Cell Biology and Physiology
Obstetrics and Gynecology

Molecular Cell Biology Program

  • 747-3457

  • 362-1984

  • 362-0186

  • 4949 Parkview, CSRB827, St. Louis, MO 63146

  • adiwan@wustl.edu

  • www.diwanlab.com

  • Lysosomes, Ischemia-reperfusion, cell death, autophagy, transcriptional regulation, metabolism

  • Transcriptional regulation of lysosome machinery under stress

Research Abstract:

Our lab is investigating the regulation of lysosome function in physiology and disease. We have found that lysosomal degradative pathways are impaired in myocardial infarction, due to impaired autophagosome-lysosome fusion and transcriptional suppression of the autophagy-lysosome machinery, resulting in cardiomyocyte death. Ongoing studies are focused upon identifying the molecular mechanisms that regulate lysosome number and function under stress, in mammalian cells and C. elegans model systems. We are developing strategies to stimulate the lysosome machinery by calorie restriction, and translate these benefits to cardioprotection in myocardial infarction. In collaborative studies, we aim to determine the efficacy of stimulating lysosome biogenesis with activation of transcription factor EB (TFEB, a master regulator of the lysosome machinery) in countering amyloid plaque pathogenesis in Alzheimer’s Disease and enhancing beta-cell survival in diabetes. In published studies in collaboration with Moley lab at Wash U, we have observed transgenrational transmission of cardiac mitochondrial abnormalities that initially result from impaired mitochondrial autophagy in the oocyte induced by maternal high fat/high sucrose diet. Our lab is now focused on understanding the heritable determinants of cardiac risk in offspring based upon maternal exposure to obesogenic diet.

Selected Publications:

Javaheri, A; Bajpai, G; Picataggi, A; Mani, S; Foroughi, L; Evie, H; Kovacs, A; Weinheimer, C; Hyrc, K; Xiao, Q; Ballabio, A; Lee, JM; Matkovich, SJ; Razani, B; Schilling, JD; Lavine, K; Diwan A. Macrophage Transcription Factor EB activation attenuates post-myocardial infarction remodeling independently of Atg5-mediated Autophagy. JCI Insight, 2019 Nov 1;4(21). pii: 127312. doi: 10.1172/jci.insight.127312

Murphy, JT*; Liu, H*; Ma, X; Shaver, S; Oh, C; Boyko, A; Mazer, T; Ang, S; Khopkar, R; Javaheri, A; Kumar, S; Jiang X; Ory, D; Mani, K; Matkovich, SJ; Kornfeld K *; Diwan A *. (*contributed equally.) Simple Nutrients Activate a HLH-30-independent Pathway for Coupling Lysosomal Nutrient Sensing to TOR Activation. PLoS Biol. 2019 May 14;17(5):e3000245.

Ferey J, Boudoures A, Reid M, Drury A, Scheaffer S, Modi Z, Kovacs A, Pietka T, DeBosch B, Thompson M, Diwan A*, and Moley K* (*contributed equally). Maternal Obesity Induces Transgenerational Cardiac Mitochondrial Dysfunction Independent of Maternal Mitochondrial Inheritance. Am J Physiol Heart Circ Physiol. 2019 Mar 22. doi: 10.1152/ajpheart.00013.2019.

Ma, X*; Mani, M*; Kovacs, A; Liu, H; Murphy, JT; Foroughi L; French, B; Benjamin, IJ; Hill, JA; Javaheri, A; Diwan A. (*contributed equally) TFEB Rescues Advanced Mutant αB-Crystallin-induced Cardiomyopathy by Normalizing Desmin Localization. J Am Heart Assoc. 2019;8:e010866. DOI: 10.1161/JAHA.118.010866.

Liu H, Javaheri A, Godar RJ, Murphy JT, Ma X, Rohatgi N, Mahadevan J, Hyrc K, Saftig P, Marshall C, McDaniel ML, Remedi MS, Razani B, Urano F, Diwan A. (*contributed equally) Intermittent Fasting Preserves Beta-cell Mass in Obesity-induced Diabetes via the Autophagy-Lysosome Pathway. Autophagy. 2017 Aug 30:0. doi: 10.1080/15548627.2017.1368596

Godar RJ, Ma X, Liu H, Murphy JT, Weinheimer CJ, Kovacs A, Crosby SD, Saftig P, Diwan A. Repetitive Stimulation of Autophagy-Lysosome Machinery by Intermittent Fasting Preconditions the Myocardium to Ischemia-Reperfusion Injury. Autophagy. 2015 Jun 23;PubMed PMID: 26103523.

Ma, X; Liu, H; Murphy, JT; Foyil SR, Godar, RJ; Abuirqeba, H; Weinheimer, CJ; Barger, PM and Diwan A. Regulation of TFEB-PGC1α Axis by BECLIN-1 Controls Mitochondrial Quality and Cardiomyocyte Death under Stress. Molecular and Cellular Biology. 2015 Mar 15;35(6):956-76. PMCID:PMC4333088

Yang KC, Ma X, Liu H, Kovacs A, Barger PM, Mann DL, Diwan A. TNF-receptor associated factor-2 mediates mitochondrial autophagy. Circulation Heart Failure. 2015 Jan;8(1):175-87. PMCID:PMC4303508

Xiao Q, Yan P, Ma X, Liu H, Perez R, Zhu A, Gonzales E, Burchett JM, Schuler DR, Cirrito JR, Diwan A*, Lee JM* (*contributed equally, co-corresponding authors). Astrocytic lysosome biogenesis facilitates Aβ clearance and attenuates amyloid plaque pathogenesis. The Journal of Neuroscience 2014: 34: 9607-9620. PMCID:PMC4099542

Ma X, Liu H, Foyil SR, Godar RJ, Weinheimer CJ, Hill JA, Diwan A. Impaired Autophagosome Clearance Contributes to Cardiomyocyte Death in Ischemia-Reperfusion Injury. Circulation. 2012 Jun 26;125(25):3170-81. PMCID:PMC3397471

Ma X, Godar RJ, Liu H, Diwan A. Enhancing lysosome biogenesis attenuates Bnip3-induced cardiomyocyte death. Autophagy. 2012 Mar 1;8(3). PMCID:PMC333784

Last Updated: 5/20/2019 8:31:06 AM

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