Our laboratory studies the interactions between metabolism and blood clot lysis. Fibrinolysis, the primary mechanism that dissolves a blood clot, is initiated by a serine protease tissue-type plasminogen activator (tPA). Our previous study discussed a novel source and regulation of endogenous basal plasma tPA derived from hepatocytes, which is important for fibrinolysis when a vessel injury occurs. The tPA activity is inhibited primarily by the serpin plasminogen activator inhibitor 1 (PAI-1). A balance between tPA and PAI-1 in plasma is essential for preventing excessive clotting. Our recent study revealed the mechanism of how hepatocytes sense metabolic stresses and imbalance the production of tPA and PAI-1, influencing the degree of impaired fibrinolysis in obesity.

The goal of our laboratory is to understand the role of hepatocyte-derived tPA and basal fibrinolysis in hemostasis, and to develop diagnostic/ preventive/ therapeutic strategies that can be used to combat atherosclerosis, thrombosis, and bleeding disorders. Specific areas of research interests include: 1) a new link between reduced fibrinolysis and dyslipidemia, 2) circadian regulation of basal fibrinolysis and the morning onset of thrombotic events, 3) the role of hepatocyte tPA and liver injuries, 4) increased fibrinolysis in hemophilia, and 5) a timely study of fibrinolysis in COVID-19.

• 2019-2022, Career Development Award, American Heart Association
• 2019-2021, ASH Fellow Scholar Award, American Society of Hematology
• 2020-2022, COVID-19 Rapid Grant from the Cullen Run Foundation, through Cardiovascular Center, Medical College of Wisconsin.
• 2020-2023, NHF Career Development Award, National Hemophilia Foundation
• 2021, ACTIV-4 COVID-19 Mechanistic Study Grant, NIH/U Mich (Co-Investigator. PI: Lisa Baumann Kreuziger, MD)
• 2021-2022, Research Pilot Award from the Michael H. Keelan, Jr., MD, Research Foundation, Cardiovascular Center, Medical College of Wisconsin (Mentor. PI: Wen Dai, MD)
• 2021-2022, ASH Supplement Award, American Society of Hematology

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3. Lee JS*, Zheng Z*, Mendez R, Ha SW, Xie Y, Zhang K. Pharmacologic ER stress induces non-alcoholic steatohepatitis in an animal model. Toxicol Lett. 2012 May 20;211(1):29-38. PMCID: PMC3334434. *Equal contributors
4. Wang G, Liu G, Wang X, Sethi S, Ali-Fehmi R, Abrams J, Zheng Z, Zhang K, Ethier S, Yang ZQ. ERLIN2 promotes breast cancer cell survival by modulating endoplasmic reticulum stress pathways. BMC Cancer. 2012 Jun 08;12:225. PMCID: PMC3732090
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7. Qiu Q, Zheng Z, Chang L, Zhao YS, Tan C, Dandekar A, Zhang Z, Lin Z, Gui M, Li X, Zhang T, Kong Q, Li H, Chen S, Chen A, Kaufman RJ, Yang WL, Lin HK, Zhang D, Perlman H, Thorp E, Zhang K, Fang D. Toll-like receptor-mediated IRE1α activation as a therapeutic target for inflammatory arthritis. EMBO J. 2013 Sep 11;32(18):2477-90. PMCID: PMC3770952
8. Zheng Z*, Zhang C*, Yan J, Ruan Y*, Zhao X, San X, Mao Y, Sun Q, Zhang K, Fan Z. Diabetes mellitus is associated with hepatocellular carcinoma: a retrospective case-control study in hepatitis endemic area. PLoS One. 2013;8(12):e84776. PMCID: PMC3873428. *Equal contributors
9. Kim H, Mendez R, Zheng Z, Chang L, Cai J, Zhang R, Zhang K. Liver-enriched transcription factor CREBH interacts with peroxisome proliferator-activated receptor α to regulate metabolic hormone FGF21. Endocrinology. 2014 Mar;155(3):769-82. PMCID: PMC3929740
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11. Zhang X, Cai J, Zheng Z, Polin L, Lin Z, Dandekar A, Li L, Sun F, Finley RL, Fang D, Yang ZQ, Zhang K. A novel ER-microtubule-binding protein, ERLIN2, stabilizes Cyclin B1 and regulates cell cycle progression Cell Discovery. 8 September 2015;1.
12. Zheng Z, Wang G, Li L, Tseng J, Sun F, Chen X, Chang L, Heng H, Zhang K. Transcriptional signatures of unfolded protein response implicate the limitation of animal models in pathophysiological studies. Environ Dis. 2016;1(1):24-30. PMCID: PMC5336312
13. Ozcan L, Ghorpade DS, Zheng Z, de Souza JC, Chen K, Bessler M, Bagloo M, Schrope B, Pestell R, Tabas I. Hepatocyte DACH1 Is Increased in Obesity via Nuclear Exclusion of HDAC4 and Promotes Hepatic Insulin Resistance. Cell Rep. 2016 06 07;15(10):2214-2225. PMCID: PMC5068925
14. Zheng Z*, Kim H*, Qiu Y, Chen X, Mendez R, Dandekar A, Zhang X, Zhang C, Liu AC, Yin L, Lin JD, Walker PD, Kapatos G, Zhang K. CREBH Couples Circadian Clock With Hepatic Lipid Metabolism. Diabetes. 2016 Nov;65(11):3369-3383. PMCID: PMC5079639. *Equal contributors
15. Dandekar A, Qiu Y, Kim H, Wang J, Hou X, Zhang X, Zheng Z, Mendez R, Yu FS, Kumar A, Fang D, Sun F, Zhang K. Toll-like Receptor (TLR) Signaling Interacts with CREBH to Modulate High-density Lipoprotein (HDL) in Response to Bacterial Endotoxin. J Biol Chem. 2016 10 28;291(44):23149-23158. PMCID: PMC5087733
16. Wang X, Zheng Z, Caviglia JM, Corey KE, Herfel TM, Cai B, Masia R, Chung RT, Lefkowitch JH, Schwabe RF, Tabas I. Hepatocyte TAZ/WWTR1 Promotes Inflammation and Fibrosis in Nonalcoholic Steatohepatitis. Cell Metab. 2016 12 13;24(6):848-862. PMCID: PMC5226184
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18. Doran AC, Ozcan L, Cai B, Zheng Z, Fredman G, Rymond CC, Dorweiler B, Sluimer JC, Hsieh J, Kuriakose G, Tall AR, Tabas I. CAMKIIγ suppresses an efferocytosis pathway in macrophages and promotes atherosclerotic plaque necrosis. J Clin Invest. 2017 Nov 01;127(11):4075-4089. PMCID: PMC5663361
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20. Ghorpade DS, Ozcan L, Zheng Z, Nicoloro SM, Shen Y, Chen E, Blüher M, Czech MP, Tabas I. Hepatocyte-secreted DPP4 in obesity promotes adipose inflammation and insulin resistance. Nature. 2018 03 29;555(7698):673-677. PMCID: PMC6021131
21. Zheng Z#, Nayak L, Wang W, Yurdagul A Jr, Wang X, Cai B, Lapping S, Ozcan L, Ramakrishnan R, Pestell RG, Jain MK, Tabas I#. An ATF6-tPA pathway in hepatocytes contributes to systemic fibrinolysis and is repressed by DACH1. Blood. 2019 02 14;133(7):743-753. PMCID: PMC6376283. #Corresponding authors
22. Cai B, Dongiovanni P, Corey KE, Wang X, Shmarakov IO, Zheng Z, Kasikara C, Davra V, Meroni M, Chung RT, Rothlin CV, Schwabe RF, Blaner WS, Birge RB, Valenti L, Tabas I. Macrophage MerTK Promotes Liver Fibrosis in Nonalcoholic Steatohepatitis. Cell Metab. 2020 02 04;31(2):406-421.e7. PMCID: PMC7004886
23. Yurdagul A Jr, Subramanian M, Wang X, Crown SB, Ilkayeva OR, Darville L, Kolluru GK, Rymond CC, Gerlach BD, Zheng Z, Kuriakose G, Kevil CG, Koomen JM, Cleveland JL, Muoio DM, Tabas I. Macrophage Metabolism of Apoptotic Cell-Derived Arginine Promotes Continual Efferocytosis and Resolution of Injury. Cell Metab. 2020 Mar 03;31(3):518-533.e10. PMCID: PMC7173557
24. Wang X, Cai B, Yang X, Sonubi OO, Zheng Z, Ramakrishnan R, Shi H, Valenti L, Pajvani UB, Sandhu J, Infante RE, Radhakrishnan A, Covey DF, Guan KL, Buck J, Levin LR, Tontonoz P, Schwabe RF, Tabas I. Cholesterol Stabilizes TAZ in Hepatocytes to Promote Experimental Non-alcoholic Steatohepatitis. Cell Metab. 2020 May 05;31(5):969-986.e7. PMCID: PMC7313619
25. Zheng Z#, Nakamura K, Gershbaum S, Wang X, Thomas S, Bessler M, Schrope B, Krikhely A, Liu RM, Ozcan L, López JA, Tabas I#. Interacting hepatic PAI-1/tPA gene regulatory pathways influence impaired fibrinolysis severity in obesity. J Clin Invest. 2020 Jul 13;130(8):4348-4359. doi: 10.1172/JCI35919. PMCID:PMC7410057. #Corresponding authors
26. Kasikara C, Schilperoort M, Gerlach B, Xue C, Wang X, Zheng Z, Kuriakose G, Dorweiler B, Zhang H, Fredman G, Saleheen D, Reilly MP, Tabas I. Deficiency of macrophage PHACTR1 impairs efferocytosis and promotes atherosclerotic plaque necrosis. J Clin Invest. 2021 Apr 15;131(8):e145275. doi: 10.1172/JCI145275. PMCID: PMC8262505
27. Dai W, Lund H, Chen Y, Zhang J, Osinski K, Jones SZ, Baumann Kreuziger L, López JA, Benjamin BJ, Silverstein RL, Zheng Z#. Hypertriglyceridemia during hospitalization independently associates with mortality in patients with COVID-19. Journal of Clinical Lipidation (accepted). #Corresponding author