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Wang Biosketch

OMB No. 0925-0001 and 0925-0002 (Rev. 10/2021 Approved Through 01/31/2026)

BIOGRAPHICAL SKETCH

NAME: Zhen Wang

eRA COMMONS USER NAME (credential, e.g., agency login): zhenwang3

POSITION TITLE: Assistant Professor

EDUCATION/TRAINING

Personal Statement

My major research interest is to understand the pathophysiology of cardiovascular diseases and to determine the molecular mechanisms of target organ injury induced by diabetes, hypertension, and obesity. My early research project was to study the mechanism of renal microcirculatory failure during sepsis-induced acute kidney injury. My research was extended to a broader area in my postdoctoral training to reveal how the CNS leptin signaling pathway differentially regulates blood pressure and metabolism in obesity. Through my academic training and research experiences, I have acquired a strong foundation in various biological disciplines, including molecular biology, pharmacology, and physiology. In addition, during my postdoctoral training, I developed my own project that NIDDK funded for a K99/R00 grant to examine the synergistic interactions of hypertension and diabetes in promoting kidney injury.

During the last few years as a principal investigator and junior faculty, my research focused on investigating how endoplasmic reticulum (ER) stress and mitochondrial dysfunction contribute to hypertensive-diabetic induced target organ injury, including nephropathy, cardiomyopathy, and neuropathy. We developed reliable surgery techniques to establish a unique diabetic-hypertensive animal model in both rats and mice. We also generated a new TRPC6 flox mouse strain to delete the TRPC6 gene with specific Cre expression in different tissues. Importantly, our group has established comprehensive methodologies that allow us to evaluate various physiological parameters, including glomerular filtration rate (GFR), cardiac systolic and diastolic function, whole-body metabolic profiles, as well as molecular and cell biological assays to examine TRPC6 activation, mitochondrial function, mitochondrial DNA variants, and cellular stress response in both in vivo and in vitro settings. Encouraging preliminary data from our research demonstrate that the global knockout of TRPC6 offers protection against renal and cardiac injury by preserving mitochondrial function in the context of diabetic-hypertensive conditions. Currently, our ongoing projects employ novel genetically engineered mouse models and pharmacological interventions to assess whether overactivation of TRPC6 mediates mitochondrial injury and apoptosis in cardiomyocytes, which contributes to cardiac damage in a model of heart failure with preserved ejection fraction (HFpEF) exposed to a combination of obesity and hypertension. The outcomes of these investigations will significantly enhance our understanding of the pathogenesis of HFpEF and potentially unveil a novel therapeutic target for the prevention or mitigation of disease progression.

Ongoing and recently completed projects:

P20GM10435 (COBRE pilot grant) John Hall (PI) 07/01/2019 Title: Role of TRPC6 channels in mediating cardiac injury in hypertension combined with diabetes

4R00DK113280-02 Zhen Wang (PI) 08/01/2018 - 07/31/2022
Title: Synergistic interactions of hypertension and diabetes in promoting kidney injury.

K99DK113280-01 Zhen Wang (PI) 05/15/2017 - 05/14/2018
Title: Synergistic interactions of hypertension and diabetes in promoting kidney injury.

Recent Papers highlighting experience studying in hypertension, diabetes and obesity-induced disease

1. Zhen Wang, Jussara M. do Carmo, Nicola Aberdein, Xinchun Zhou, Jan M. Williams, Alexandre A. da Silva, John E. Hall. Synergistic Interaction of Hypertension and Diabetes in Promoting Kidney Injury and the Role of Endoplasmic Reticulum Stress. 2017; May;69(5):879-891.
2. Zhen Wang, Jussara M. do Carmo, Alexandre A. da Silva, Yiling Fu, Lance T. Jaynes, Jaylan Sears, Xuan Li, Alan J. Mouton, Ana Carolina M. Omoto, Brittney P. Xu and John E. Hall. Transient receptor potential cation channel 6 (TRPC6) deficiency leads to increased body weight and metabolic dysfunction. Am J Physiol-Regulatory, Integrative and Comparative. Jun 2022.
3. Zhen Wang, Yiling Fu, Jussara M. do Carmo, Alexandre A. da Silva, Xuan Li, Alan Mouton, Ana Carolina M. Omoto, Jaylan Sears, and John E. Hall. Transient receptor potential cation channel 6 contributes to kidney injury induced by diabetes and hypertension. Am J Physiol- Renal Physiol.2022 Jan 1;322(1):F76-F88.
4. Xuan Li, Elizabeth R. Flynn, Jussara M. do Carmo, Zhen Wang, Alexandre A. da Silva, Alan J. Mouton, Ana C. M. Omoto, Michael E. Hall and John E. Hall. Direct Cardiac Actions of Sodium-Glucose Cotransporter 2 Inhibition Improve Mitochondrial Function and Attenuate Oxidative Stress in Pressure Overload-Induced Heart Failure. Cardiovasc. Med, 12 May 2022

Positions, Scientific Appointments, and Honors

Positions and Employment

ACTIVITY/ OCCUPATION	START DATE MM/YYYY	END DATE MM/YYYY	FIELD	INSTITUTION/ COMPANY
Assistant Professor	08/2018	Present	Physiology	Department of Physiology and Biophysics, University of Mississippi Medical Center,
Instructor	01/2014	07/2018	Physiology	Department of Physiology and Biophysics, University of Mississippi Medical Center,
Research Assistant	6/2005	6/2007	Molecular Biology	Cardiology Division, Department of Internal Medicine, University of Arkansas for Medical Sciences
Medical Technologist	06/1999	03/2001	Pathology	Landing Early Cancer Diagnosis Center

Other Experiences and Professional Memberships

2008-2012 American Society for Pharmacology and Experimental Therapeutics

2012- American Heart Association

2012- American Physiological Society

Academic and Professional Honors

2014 Showcase presentation in the KCVD Young Investigator Symposium, ASN, Kidney Week

2015 APS Caroline tum Suden/Francis A. Hellebrandt Professional Opportunity Award, Experimental Biology

2017 Trustmark Postdoctoral Publication Award, School of Graduate Studies in the Hearth Sciences

Contributions to Science

Early career: My graduate research was focused on understanding the biochemical and physiological mechanisms triggered by sepsis that lead to cellular injury and organ failure in animal models of sepsis-induced acute kidney injury. I found that the development of oxidative stress in the peritubular capillary microenvironment mediates sepsis-induced renal microcirculatory failure and acute kidney injury. I also reported new therapeutic approaches to prevent sepsis-induced renal injury by targeting Sphingosine-1-Phosphate receptor 1 and mitochondrial-generated ROS production. During my Ph.D. studies, I developed a new technique with intravital video microscopy to assess mitochondrial oxidant production and measure peritubular capillary perfusion in vivo. I also learned techniques for measuring renal blood flow, glomerular filtration rate in the mouse, and immunohistochemistry/immunofluorescence techniques.

1. Zhen Wang, Christan Herzog, Gur P. Kaushal, Neriman Gokden, Philip R. Mayeux. Actinonin, a meprin A inhibitor, protects the renal microcirculation during sepsis. 2011 Feb;35(2):141-147.
2. Joseph H. Holthoff, Zhen Wang, Kathryn A. Seely, Neriman Gokden, Philip R. Mayeux. Resveratrol improves renal microcirculation, protects the tubular epithelium and prolongs survival in a mouse model of sepsis-induced acute kidney injury. Kidney Int. 2012 Feb;81(4):370-378.
3. Zhen Wang,Joseph H. Holthoff, Kathryn A. Seely, Horace J. Spencer, III, Neriman Gokden,Philip R. Mayeux. Development of oxidative stress in the peritubular capillary microenvironment mediates sepsis-induced renal microcirculatory failure and acute kidney injury. Am J Pathol. 2012 Feb;180(2):505-516.
4. Zhen Wang, Clark R. Sims, Naeem K. Patil, Neriman Gokden and Philip R. Mayeux. Pharmacological Targeting of Sphingosine-1-Phosphate Receptor 1 Improves the Renal Microcirculation During Sepsis in the Mouse. J Pharmacol Exp Ther. 2015 January:352:61–66.

Postdoctoral/ Instructor Training: During my postdoctoral period, my project was to examine the role of negative regulators of leptin signaling (SOCS3) in modulating leptin’s metabolic and cardiovascular functions in POMC neurons. I found that selective deletion of SOCS3 in POMC neurons amplifies the blood pressure response to a high-fat diet and acute stress but has minimal effects on metabolic functions. From this project, I gained more experience in animal surgical procedures and measuring cardiac-renal function.

1. Nicola Aberdein, Robert J Dambrino, Jussara M. do Carmo, Zhen Wang, Laura E Mitchell, Heather A Drummond, and John E. Hall. Role of PTP1B in POMC neurons during chronic high-fat diet: sex differences in regulation of liver lipids and glucose tolerance. Am J Physiol-Regulatory, Integrative and Comparative Physiology. 2018; Mar 1;314(3):R478-R488
2. Jussara M. do Carmo, Alexandre A. da Silva, John Nathan Freeman, Zhen Wang, Sydney P. Moak, Michael W. Hankins, Heather A. Drummond, John E. Hall. Neuronal SOCS3 (Suppressor of Cytokine Signaling 3) Role in Modulating Chronic Metabolic and Cardiovascular Effects of Leptin. Hypertension. 2018; 71:00-00
3. Zhen Wang, Jussara M. do Carmo, Alexandre A. da Silva, Kandice C. Bailey, Nicola Aberdein, Sydney P. Moak, and John E. Hall. Role of SOCS3 in POMC Neurons in Metabolic and Cardiovascular Regulation. Am J Physiol-Regulatory, Integrative and Comparative Physiology. 2019; 316: R338–R351.

Junior faculty research in kidney injury: My current research program investigates the molecular mechanisms of hypertensive-diabetic renal and cardiac injury. I found that hypertension interacts synergistically with diabetes to promote renal injury by initiating a positive feedback loop, including mitochondrial dysfunction, ER stress, and oxidative stress. I also found that deletion of TRPC6 markedly attenuated renal dysfunction and reduced apoptotic cell injury in glomeruli exposed to hyperglycemia and high blood pressure.

1. Zhen Wang, Jussara M. do Carmo, Nicola Aberdein, Xinchun Zhou, Jan M. Williams, Alexandre A. da Silva, John E. Hall. Synergistic Interaction of Hypertension and Diabetes in Promoting Kidney Injury and the Role of Endoplasmic Reticulum Stress. 2017; May;69(5):879-891.
2. Zhen Wang, Jussara M. do Carmo, Alexandre A. da Silva, Yiling Fu and John E. Hall. Mechanisms of synergistic interactions of diabetes and hypertension in chronic kidney disease: role of mitochondrial dysfunction and ER stress. Current Hypertension Reports. 2020. Feb 3;22(2):15.
3. Zhen Wang, Jussara M. do Carmo, Alexandre A. da Silva, Yiling Fu, Lance T. Jaynes, Jaylan Sears, Xuan Li, Alan J. Mouton, Ana Carolina M. Omoto, Brittney P. Xu and John E. Hall. Transient receptor potential cation channel 6 (TRPC6) deficiency leads to increased body weight and metabolic dysfunction. AJP-Regulatory, Integrative and Comparative. Jun 2022.
4. Zhen Wang, Yiling Fu, Jussara M. do Carmo, Alexandre A. da Silva, Xuan Li, Alan Mouton, Ana Carolina M. Omoto, Jaylan Sears, and John E. Hall. Transient receptor potential cation channel 6 contributes to kidney injury induced by diabetes and hypertension. Am J Physiol Renal Physiol.2022 Jan 1;322(1):F76-F88.

Junior faculty research area in cardiac injury: I am currently expanding my research to encompass a broader area, focusing on exploring the involvement of TRPC6 channels in mediating metabolic abnormalities, particularly related to mitochondrial bioenergetics, across multiple organs such as the kidney, heart, and brain within the context of conditions such as diabetes, hypertension, and obesity.

1. Jussara M. do Carmo, Ana C. M. Omoto, Xuemei Dai, Sydney P. Moak, Gabriela S. Mega, Xuan Li, Zhen Wang, Alan J. Mouton, John E. Hall, and Alexandre A. da Silva. Sex differences in the impact of parental obesity on offspring cardiac SIRT3 expression, mitochondrial efficiency and diastolic function early in life. Am J Physiol-Heart Circ Physiol. 2021 Sep 1;321(3):H485-H495.
2. Xuan Li, Elizabeth R. Flynn, Jussara M. do Carmo, Zhen Wang, Alexandre A. da Silva, Alan J. Mouton, Ana C. M. Omoto, Michael E. Hall and John E. Hall. Direct Cardiac Actions of Sodium-Glucose Cotransporter 2 Inhibition Improve Mitochondrial Function and Attenuate Oxidative Stress in Pressure Overload-Induced Heart Failure. Cardiovasc. Med, 12 May 2022
3. Ana C. M. Omoto, Jussara M. do Carmo, Benjamin Nelson, Nikaela Aitken, Xuemei Dai, Sydney Moak, Elizabeth Flynn, Zhen Wang, Alan J. Mouton, Xuan Li, John E. Hall and Alexandre A. da Silva. Central Nervous System Actions of Leptin Improve Cardiac Function After Ischemia–Reperfusion: Roles of Sympathetic Innervation and Sex Differences. JAHA, 27 Oct 2022.
4. Alan Mouton, Nikaela M Aitken, Sydney P Moak, Jussara Marcia Do Carmo, Alexandre A. da Silva, Ana Carolina Mieko Omoto, Xuan Li, Zhen Wang and John Hall. Temporal changes in glucose metabolism reflect polarization in resident and monocyte-derived macrophages after myocardial infarction. Cardiovasc. Med, April 2023. In publish.

Complete List of Published Work in MyBibliography: https://www.ncbi.nlm.nih.gov/sites/myncbi/1497cnWDxtw/bibliography/40776773/public/?sort=date&direction=ascending