Our laboratory studies the interactions between lipoprotein 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 (Blood, 2019). 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 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 (JCI, 2020). 

A new study from our lab, discovered a direct interaction between tPA and apoB, the scaffold protein of LDL and VLDL particles, reducing VLDL production from hepatocytes and lowering atherogenic apoB-lipoprotein cholesterol in circulation (Science, 2023). 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 in atherothrombosis, 2) fibrinolysis and lipoproteins in hemophilia, 3) the role of lipoprotein in platelet biology, 4) the role of hepatocyte tPA and liver injuries, and 5) a timely study of dyslipidemia and thrombosis 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
• 2022-2023, Joan Gill Pilot Award, Versiti
• 2022-2027, NIH R01 HL163516
• 2022-2025, AHA Collaborative Science Award, American Heart Association

1. Laing S, Wang G, Briazova T, Zhang C, Wang A, Zheng Z, Gow A, Chen AF, Rajagopalan S, Chen LC, Sun Q, Zhang K. Airborne particulate matter selectively activates endoplasmic reticulum stress response in the lung and liver tissues. American J Physiology-Cell Physiology. 2010 Oct;299(4):C736-49. PMCID: PMC2957267.
2. Zhang C, Wang G, Zheng Z, Maddipati KR, Zhang X, Dyson G, Williams P, Duncan SA, Kaufman RJ, Zhang K. Endoplasmic reticulum-tethered transcription factor cAMP responsive element-binding protein, hepatocyte specific, regulates hepatic lipogenesis, fatty acid oxidation, and lipolysis upon metabolic stress in mice. Hepatology. 2012 Apr;55(4):1070-82. PMCID: PMC3319338.
3. Lee JS*, Zheng Z*, Mendez R, Ha SW, Xie Y, Zhang K. Pharmacologic ER stress induces non-alcoholic steatohepatitis in an animal model. Toxicology Letters. 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.
5. Zheng Z, Xu X, Zhang X, Wang A, Zhang C, Hüttemann M, Grossman LI, Chen LC, Rajagopalan S, Sun Q, Zhang K. Exposure to ambient particulate matter induces a NASH-like phenotype and impairs hepatic glucose metabolism in an animal model. Journal of Hepatology. 2013 Jan;58(1):148-54. PMCID: PMC3527686.
6. Mendez R, Zheng Z, Fan Z, Rajagopalan S, Sun Q, Zhang K. Exposure to fine airborne particulate matter induces macrophage infiltration, unfolded protein response, and lipid deposition in white adipose tissue. American J Translational Research. 2013;5(2):224-34. PMCID: PMC3612517.
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 Journal. 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.
10. Zheng Z, Zhang X, Wang J, Dandekar A, Kim H, Qiu Y, Xu X, Cui Y, Wang A, Chen LC, Rajagopalan S, Sun Q, Zhang K. Exposure to fine airborne particulate matters induces hepatic fibrosis in murine models. Journal of Hepatology. 2015 Dec;63(6):1397-404. PMCID: PMC5003300.
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. Environmental Disease. 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 Reports. 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 Biological Chemistry. 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 Metabolism. 2016 12 13;24(6):848-862. PMCID: PMC5226184.
17. Kim H*, Zheng Z*, Walker PD, Kapatos G, Zhang K. CREBH Maintains Circadian Glucose Homeostasis by Regulating Hepatic Glycogenolysis and Gluconeogenesis. Molecular and Cellular Biology. 2017 07 15;37(14). PMCID: PMC5492176. *Equal contributors.
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. Journal of Clinical Investigation. 2017 Nov 01;127(11):4075-4089. PMCID: PMC5663361.
19. Qiu Y, Zheng Z, Kim H, Yang Z, Zhang G, Shi X, Sun F, Peng C, Ding Y, Wang A, Chen LC, Rajagopalan S, Sun Q, Zhang K. Inhalation Exposure to PM2.5 Counteracts Hepatic Steatosis in Mice Fed High-fat Diet by Stimulating Hepatic Autophagy. Scientific Reports. 2017 11 24;7(1):16286. PMCID: PMC5701159.
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 Metabolism. 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 Metabolism. 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 Metabolism. 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. Journal of Clinical Investigation. 2020 Jul 13. PMCID: PMC32657780. #Corresponding authors.
26. Canan Kasikara, Maaike Schilperoort, Brennan D Gerlach, Chenyi Xue, Xiaobo Wang, Ze Zheng, George Kuriakose, Bernhard Dorweiler, Hanrui Zhang, Gabrielle Fredman, Danish Saleheen, Muredach P Reilly, Ira Tabas. Deficiency of macrophage PHACTR1 impairs efferocytosis and promotes atherosclerotic plaque necrosis. Journal of Clinical Investigation. 2021 Feb 25. PMCID: PMC33630758.
27. Zheng Z#, Zhang K#. Inter‑3’ ends CpG islands are enriched in human chromosome 19p13.3 region: A genomic signature of metabolism‑associated genes. Environmental Disease. 2021, 6, 1 [p. 24-29]. DOI: 10.4103/ed.ed_4_21. #Corresponding authors.
28. 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 Lipidology. 2021 Sep-Oct;15(5):724-731. PMCID: PMC8353976.
29. Durani U, Major A, Velazquez AI, May J, Nelson M, Zheng Z, Hall AG, Alam ST, Reynolds R, Thompson JC, Kumbamu A, Das DG, Murphy MC, Henry E, Lee AI, Marshall AL, Wun T, Weeks LD. Impact of COVID-19 on Hematology-Oncology Trainees: A Quantitative and Qualitative Assessment. JCO Oncology Practice. 2022 Jan 6:OP2100630. PMID: 34990292, PMCID: PMC9014488.
30. Rodriguez M, Dai W, Lund H, Osinski K, Zhang Z, Silverstein R, Zheng Z. The correlations among racial/ethnic groups, hypertriglyceridemia, thrombosis, and mortality in hospitalized patients with COVID-19. Best Practice & Research: Clinical Haematology. 2022 Sep;35(3):101386. Epub 2022 Oct 3. PMID: 36494155.
31. Shi H, Wang X, Li F, Gerlach BD, Yurdagul A Jr, Moore MP, Zeldin S, Zhang H, Cai B, Zheng Z, Valenti L, Tabas I. CD47-SIRPα axis blockade in NASH promotes necroptotic hepatocyte clearance by liver macrophages and decreases hepatic fibrosis. Science Translational Medicine. 2022 Nov 23;14(672):eabp8309. Epub 2022 Nov 23. PMID: 36417485.
32. Zhang J, Chang J, Beg MA, Huang W, Zhao Y, Dai W, Wu X, Cui W, Pillai SS, Lakhani HV, Sodhi K, Shapiro JI, Sahoo D, Zheng Z, Silverstein RL, Chen Y. Na/K-ATPase suppresses LPS-induced pro-inflammatory signaling through Lyn. iScience. 2022 Aug 17;25(9):104963. eCollection 2022 Sep 16. PMID: 36072548
33. Furon J, Yetim M, Pouettre E, Martinez de Lizarrondo S, Maubert E, Hommet Y, Lebouvier L, Zheng Z, Ali C, Vivien D. Blood tissue Plasminogen Activator (tPA) of liver origin contributes to neurovascular coupling involving brain endothelial N-Methyl-D-Aspartate (NMDA) receptors. Fluids Barriers CNS. 2023 Feb 3;20(1):11. PMID: 36737775.
34. Puzyrenko A, Jacobs ER, Padilla N, Devine A, Aljadah M, Gantner BN, Pan AY, Lai S, Dai Q, Rubenstein JC, North PE, Simpson PM, Willoughby RE, O'Meara CC, Flinn MA, Lough JW, Ibrahim EH, Zheng Z, Sun Y, Felix J, Hunt BC, Ross G, Rui H, Benjamin IJ. Collagen-Specific HSP47+ Myofibroblasts and CD163+ Macrophages Identify Profibrotic Phenotypes in Deceased Hearts With SARS-CoV-2 Infections. J American Heart Association. 2023 Feb 21;12(4):e027990. doi: 10.1161/JAHA.122.027990. Epub 2023 Feb 15. PMID: 36789856.
35. Dai W, Zhang H, Lund, H, Zhang Z, Castleberry M, Rodriguez M, Kuriakose G, Gupta S, Lewandowska M, Powers HR, Valmiki S, Zhu J, Shapiro AD, Hussain MM, Lopez JA, Sorci-Thomas MG, Silverstein RL, Ginsberg HN, Sahoo D, Tabas IA, Zheng Z. Intracellular tPA-PAI-1 Interaction Determines VLDL Assembly in Hepatocytes. Sept 2023. Science. PMID: 37651538.
36. Zhang Z, Dai W, Zhu W, Rodriguez M, Lund H, Xia Y, Chen Y, Rau M, Schneider EA, Graham MB, Jobe S, Wang D, Wen R, Whiteheart SW, Wood JP, Silverstein R, Berger JS, Kreuziger LB, Barrett T, Zheng Z. Plasma tPA levels associate with apolipoprotein(a) and clinical outcomes in hospitalized COVID-19 patients. Research and Practice on Thrombosis and Haemostasis (RPTH). Aug. 2023. PMID: 37680312.

Books, Chapters, Editorials, Guidelines, and Reviews

1. Zheng Z, Zhang C, Zhang K. Role of unfolded protein response in lipogenesis. World J Hepatology. 2010 Jun 27;2(6):203-7. PMCID: PMC2999286. Review.
2. Zheng Z, Zhang C, Zhang K. Measurement of ER stress response and inflammation in the mouse model of nonalcoholic fatty liver disease. Methods in Enzymology. 2011;489:329-48. Book Chapter.
3. Yang Z, Kim H, Ali A, Zheng Z, Zhang K. Interaction between stress responses and circadian metabolism in metabolic disease. Liver Research. 2017 Sep;1(3):156-162. PMCID: PMC5805151. Review.
4. Ze Zheng#, Xiaobo Wang, Bishuang Cai: A review of nonalcoholic fatty liver disease - genetics and animal models. Environmental Disease, 07/2016. Review. #Corresponding authors
5. Zheng Z, Riva N, Scarlatescu E, de Moerloose P, Ariëns R, Amigo MC; ISTH Ethics Committee. Developing and improving the ethical framework for the ISTH. J Thrombosis and Haemostasis. 2022 Aug;20(8):1753-1754. PMID: 35859283. Guest Editorial.
6. Nayak L#, Zheng Z#. COVID-19: A hematological perspective. Best Practice & Research: Clinical Haematology. 2022 Sep;35(3):101412. Epub 2022 Nov 4. PMID: 36494151. Guest Editorial. #Corresponding authors, equal contribution.
7. Zheng Z, Mukhametova L, Boffa MB, Moore EE, Wolberg AS, Urano T, Kim PY. Assays to quantify fibrinolysis: strengths and limitations. Communication from the International Society on Thrombosis and Haemostasis Scientific and Standardization Committee on fibrinolysis. J Thrombosis Haemostasis. 2023 Apr;21(4):1043-1054. doi: 10.1016/j.jtha.2023.01.008. Epub 2023 Jan 14. PMID: 36759279. Recommendations and Guidelines.
8. Kahn SR, Arnold DM, Casari C, Desch KC, Devreese KMJ, Favaloro EJ, Gaertner F, Gouw SC, Gresele P, Griffioen AW, Heger L, Kini RM, Kohli S, Leader A, Lisman T, Lordkipanidzé M, Mullins E, Okoye HC, Rosovsky RP, Salles-Crawley II, Selby R, Sholzberg M, Stegner D, Violi F, Weyand AC, Williams S, Zheng Z. Illustrated State-of-the-Art Capsules of the ISTH 2023 Congress. Res Pract Thromb Haemost. 2023 Jun 21;7(4):100193. PMID: 37538494.
9. Dai W, Castleberry M, Zheng Z. Tale of two systems: the intertwining duality of fibrinolysis and lipoprotein metabolism. J Thromb Haemost. 2023 Aug 12:S1538-7836(23)00628-1. PMID: 37579878.
10. Yin L, Zhou T, Zheng Z, Long X, Qiu H, Lu HS. Editorial: Women in cardiovascular therapeutics. Front Cardiovasc Med. 2023 May 10;10:1183427. PMID: 37234374.

Non-peer reviewed educational products

1. Bishuang Cai, Ze Zheng. Run a Marathon on Rolling Hills - Career Transition in the Pandemic Era. American Society of Hematology TraineE-News, May 2020.
2. Lalitha Nayak, Ze Zheng. It Takes Two to Tango: How to Be a Great Mentee. American Society of Hematology TraineE-News, Feb 2020.
3. Ze Zheng. Where Can ASH Awards Take You? Stories from the ASH Early-Career Awardees. American Society of Hematology TraineE-News, Nov 2019.
4. Ze Zheng, Andrew Volk, Jeremy Wood. The road from postdoc to independent investigator. American Society of Hematology TraineE-News, May 2019.