Liya Pi, PhD

Assistant Professor

School of Medicine
Department
Pathology Laboratory Medicine
LIya Pi

Education & Affiliations

1992 B.S., Biology, Lanzhou University China
2000 M.S., Biochemistry & Molecular Biology, University of California Davis
2005 Ph.D., Molecular Cell Biology, University of Florida Gainesville

Biography

Appointment and Positions

  • 2012-2019 - Research Assistant Professor, Department of Pediatrics, University of Florida Gainesville
  • 2020-2021 - Assistant Professor (Tenure-track), Department of Pediatrics, University of Florida Gainesville
  • 2021-Present - Assistant Professor (Tenure-track), Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA

Research

Liver fibrosis and its advanced form cirrhosis can occur in virtually all types of chronic liver disease (CLD) and are major health problems as they cause high mortality rates and a predisposition to liver failure, portal hypertension, and hepatocellular carcinoma (HCC). Failure to regenerate in hepatocytes eventually causes replacement of functional parenchyma with extensive scar tissues. Hepatic progenitor cells (HPCs) are the source of an alternative regenerative mechanism that is activated when hepatocyte proliferation is inhibited due to severe liver damage. HPCs are intimately associated with activated hepatic stellate cells (HSC) during advanced fibrosis and cirrhosis. A current epidemic of end-stage CLD related to cirrhosis has precipitated the urgent need for anti-fibrotic therapies. The long-term goal in Pi’s research is to understand mechanisms underlying liver repair and to develop novel therapies that would prevent HPC activation and reverse liver fibrosis. There are three ongoing projects in Pi’s laboratory

Project 1:  Understanding connective tissue growth factor (Ctgf/Ccn2) and its regulation during liver repair
Connective tissue growth factor (Ctgf/Ccn2) belongs to a class of extracellular signaling modulators of the Cyr61/CTGF/Nov protein family that regulates cell adhesion, migration, differentiation, and apoptosis. We have demonstrated that Ctgf/Ccn2 is upregulated in several tissues including liver, retina and cornea using rodent injury models. This gene is induced in response to hypoxia and regulates multiple angiogenic pathways by binding to a structurally conserved cysteine knot motif present in growth factors of the cysteine knot superfamily. Overexpression of this gene contributes to Lewis lung carcinoma whereas interference with its activity inhibits the tumorigenesis and angiogenesis. 
In the liver, we have demonstrated that Ctgf/Ccn2 induction occurs as common mechanism during multiple types of injury. This matricellular protein can be regulated at transcriptional levels by hepatocyte nuclear factor (Hnf) 4α and Yes-associated protein (Yap), two transcriptional regulators that control hepatocytes and HPC phenotype respectively. Given the fact that Ctgf/Ccn2 overexpression has been found in hepatocytes during steatohepatitis, cirrhosis, and liver cancer development, we hypothesize that it promotes HCC development through direct effect on hepatocytes, the primary cell type to form HCC tumor cells after transformation. Its actions on HPC, stellate cells, and vascular endothelial cells also contribute to the formation of fibrotic and pro-tumorigenic microenvironment leading to inflammation, fibrosis, and HCC development. We test this hypothesis using two murine models of HCC. One model involves dietary and chemical interventions through the feeding of high fat diet (HFD) in combination with the diabetic inducer streptozotocin. This model induces nonalcoholic steatohepatitis (NASH)-associated HCC in diabetic mice. By replacing HFD with ethanol containing liquid diet, we reproducibly induce alcoholic steatohepatitis (ASH)-associated HCC under diabetic conditions in animals. Moreover, we have generated Ctgf/Ccn2 knockouts in hepatocytes using albumin-promoter driven Cre (Alb-Cre), in vascular endothelial cells using VE-cadeherin-promoter driven Cre (VECAD-Cre), and in myeloid cells using lysozyme 2-promoter driven Cre (Lyz-Cre). All the animal models established in our laboratory are powerful tools and allow us to dissect cell specific functions of Ctgf/Ccn2 gene in HPC activation, liver fibrosis, and HCC development.

Project 2:  Roles of Adamts7 in hepatic progenitor cell activation, liver fibrosis, and liver cancer development
Adamts7 (a disintegrin and metalloproteinase with thrombospondin type I repeat 7) belongs to the ADAMTS family of zinc-dependent protease. It is a novel protease for Ctgf/Ccn2 and a new player in liver fibrosis. We have shown upregulation of Adamts7 and Ctgf/Ccn2 in hepatocytes and myofibroblast cells within HPC niches. Adamts7 deficiency increases Ctgf/Ccn2 accumulation, enhances HPC activation, and promotes biliary fibrosis. Our recent RNA sequencing analysis identified Adamts7 as one of under-represented genes after liver injury following alcohol binge or chronic-on-binge. To fully understand the function of Adamts7, we have developed knockout mice and inactivate this enzyme in cells and animals. It is anticipated that alteration of this key enzyme will affect the biological activity or availability of Ctgf/Ccn2, change hepatic inflammatory responses, HSC activation, liver fibrosis, HPC activation, and liver cancer development. 

Project 3:  Roles of extracellular matrix protein 1 (Ecm1) in hepatic progenitor cell activation, liver fibrosis, and liver cancer development
Extracellular matrix protein (Ecm)1 is a secreted glycoprotein with inhibitory functions in transforming growth factor (Tgf)-β activation via blocking αv integrin. In contrast, Ctgf/Ccn2 promotes Tgf-β activation via binding to αvβ6 integrin and fibronectin. Our preliminary data showed that Ecm1 could bind to αvβ6 integrin and Ctgf/Ccn2 leading to inhibition of Tgf-β activation. Moreover, Ecm1 was downregulated during liver fibrosis and alcoholic hepatitis in experimental and human studies. We hypothesize that ectopic Ecm1 has anti-fibrotic potentials by competing with Ctgf/Ccn2 for αv integrin binding and reduces Tgf-β activation. To test this hypothesis, we will overexpress Ecm1 using AAV8 delivery system in vitro and in vivo. It is expected that Ecm1 overexpression masks Ctgf/Ccn2 and the integrin receptors, decreases Tgf-β activation, and reduces inflammation, fibrosis, HPC activation, and liver cancer development in chronic liver disease.

Patent 
Mouse model of alcohol-induced liver cancer 
Inventor: Liya Pi
U.S. Provisional Appl. No. 63/093,462 filed October 19, 2020
A&B Ref. 049648/695467
UF Ref. T18330US001
 

Grants

  • Current:
    • RO1AA028035 NIH/NIAAA                              Pi (PI)          2/1/2020-1/31/2025    
      Regulation of the pro-fibrotic connective tissue growth factor in alcoholic liver disease: mechanisms and targeting approaches
      This grant examines the mechanisms and targeting approaches of alcoholic liver disease related to CTGF and its two signal partners ADAMTS7 and ECM1 
       
  • Completed:
    • K01AA024174 NIH/NIAAA                          Pi (PI)         2/1/2016-1/31/2021    
      Connective Tissue Growth Factor (CTGF): An Intriguing Therapeutic Target in Alcoholic Fibrosis
      This grant examines the pathway and therapeutic potentials of fibrosis regulated by CTGF and microRNA 133b due to alcohol exposure.
    • Chris DiMarco Institutional Research Grant (ACS-IRG) American Cancer Society                          Pi (PI)              8/1/2014-7/31/2015
      Roles of Connective Tissue Growth Factor for the Development of Liver Cancer in the Setting of Metabolic Syndrome
      The major goals are to investigate the importance of CTGF in liver cancer under the background of insulin resistance and nonalcoholic steatohepatitis.
      Role: PI
    • Children Miracle Network Foundation/Pilot Studies Grant                          Pi (PI)          07/01/2013-06/30/2021
      Using Knockout Mouse Models to Investigate the Roles of Connective Tissue Growth Factor and Its Processing Enzyme ADAMTS7 in Tissue Repair
      The major goals are to investigate the function of CTGF and ADAMTS7 in liver repair and to understand the regulation of CTGF biological activity by ADAMTS7 enzyme. 
      Role: PI

Contributions

Selective Publications

  • Zhou J, Sun X, Yang L, Wang L, Ran G, Wang J, Cao Q, Wu L, Bryant A, Ling C, Pi L. Hepatocyte Nuclear Factor 4α negatively Regulates Connective Tissue Growth Factor During Liver Regeneration. The FASEB Journal. 2020;00:1-14.
  • Chen M, Sun X, Wei W, Cucarella C, Martín-Sanz P, Casado M, Pi L, Ren B, Cao Q. Hepatic COX-2 expression protects mice from an alcohol-high fat diet-induced metabolic disorder by involving protein acetylation related energy metabolism. Alcohol. 2021 92:41-52.
  • Oliveira AC, Fu C, Lu Y, Williams MA, Pi L, Brantly ML, Ventetuolo CE, Raizada MK, Mehrad B, Scott EW, Bryant AJ. Chemokine signaling axis between endothelial and myeloid cells regulates development of pulmonary hypertension associated with pulmonary fibrosis and hypoxia. Am J Physiol Lung Cell Mol Physiol. 2019 1;317(4):L434-L444.
  • Li S, Sun X, Chen M, Ying Z, Wan Y, Pi L, Ren B, Cao Q. Liver Fibrosis Conventional and Molecular Imaging Diagnosis Update. Journal of liver. 2019 8(1):236.
  • Cao Q, Xu S, Li S, Chen M, Sun X, Wan Y, Pi L, Ying Z, Ren B. Quantification of Hepatic Lipid Using 7.0T Proton Magnetic Resonance Spectroscopy and Computed Tomography in Mild Alcoholic Steatotic Mice. J Liver. 2018;7(4). 
  • Pi L, Fu C, Lu Y, Zhou J, Jorgensen M, Shenoy V, Lipson KE, Scott EW, Bryant AJ. Vascular Endothelial Cell-Specific Connective Tissue Growth Factor (CTGF) is Necessary for Development of Chronic Hypoxia-Induced Pulmonary Hypertension. Frontiers Physiology Journal 2018 9:138.
  • Xu S, Zhu W, Wan Y, Wang J, Chen X, Pi L, Lobo MK, Ren B, Ying Z, Morris M, Cao Q. Decreased Taurine and Creatine in the Thalamus May Relate Behavioral Impairments in Ethanol-fed Mice: A Pilot Study of Proton Magnetic Resonance Spectroscopy. Molecular Imaging. 2018 17:1536012117749051.
  • Bria A, Marda J, Zhou J, Sun X, Cao Q, Petersen BE, Pi L. Hepatic Progenitor Cell Activation in Liver Repair. The Liver Research Journal 2017 1(2):81-87.
  • Wu Q, Pi L, Trinh T, Zuo C, Xia M, Jiao Y, Puszyk W, Pham K, Nelson D, Robertson K, Ostrov D, Xia C, Liu C. Vaccine targeting glypican-3 induces tumor regression in a murine hepatocellular carcinoma model. Molecular Therapy. 2017 25(10):2299-2308.
  • Feng X, Pi L, Sriram S, Schultz G, Gibson D. Connective tissue growth factor is not necessary for haze formation in excimer laser wounded mouse corneas. PLOS ONE. 2017 16;12(2):e0172304. 
  • Wu QF, Jorgensen M, Song J, Zhou JM, Liu C, and Pi L, Members of the Cyr61/CTGF/NOV Protein Family: Emerging Players in Hepatic Progenitor Cell Activation and Intrahepatic Cholangiocarcinoma. Gastroentrology Research and Practice. 2016;2016:2313850.
  • Gjymishka A, Pi L, Oh SH, Jorgensen M, Liu C, Protopapadakis Y, Patel A, and Petersen BE. The microRNA 133b regulation of connective tissue growth factor: a novel mechanism in liver pathology. American Journal Pathology. 2016 186(5):1092-102. 
  • Robinson PM, Pi L, Brown A, Sullivan DC, and Petersen BE. Introduction to hepatic progenitor cells. Book: Liver Regeneration. Basic Mechanisms, Relevant Models and Clinical Applications. 2016 Chapter 17. Page 245-250. Edited by: Udayan M. Apte. ISBN: 978-0-12-420128-6. Elsevier Inc.
  • Pi L, Chung PY, Sriram S, Rahman MM, Song WY, Scott EW, Petersen BE, Schultz GS. Connective tissue growth factor differentially binds to members of the cystine knot superfamily and potentiates platelet-derived growth factor-B signaling in rabbit corneal fibroblast cells. World J Biol Chem 2015 6(4): 379-388.
  • Pi L, Jorgensen M, Oh SH, Protopapadakis Y, Gjymishka A, Brown A, Robinson P, Liu C, Scott EW, Schultz GS, Petersen BE. A disintegrin and metalloprotease with thrombospondin type i motif 7: a new protease for connective tissue growth factor in hepatic progenitor/oval cell niche. American Journal Pathology. 2015 185(6):1552-1563.
  • Pi L, Robinson PM, Jorgensen M, Oh SH, Brown AR, Weinreb PH, Trinh TL, Yianni P, Liu C, Leask A, Violette SM, Scott EW, Schultz GS, Petersen BE. Connective tissue growth factor and integrin αvβ6: a new pair of regulators critical for ductular reaction and biliary fibrosis in mice. Hepatology. 2015 61(2):678-691.
  • Sriram S, Gibson DJ, Robinson P, Pi L, Lewin AS, Schultz G. Assessment of anti-scarring therapies in ex vivo organ cultured rabbit corneas. . Experiment Eye Research. 2014 125C:173-182.
  • Gibson DJ, Pi L, Sriram S, Mao C, Petersen BE, Scott EW, Leask A, Schultz GS. Conditional knockout of CTGF affects corneal wound healing. Invest Ophthalmol Vis Sci. 2014 55(4):2062-70. 
  • Sriram S, Robinson P, Pi L, Lewin AS, Schultz G. Triple combination of siRNAs targeting TGFβ1, TGFβR2 and CTGF enhances reduction of collagen I and smooth muscle actin in corneal fibroblasts. Invest Ophthalmol Vis Sci. 2013 54(13):8214-23.
  • Robinson PM, Chuang TD, Sriram S, Pi L, Luo XP, Petersen BE, Schultz GS. MicroRNA signature in wound healing following excimer laser ablation: role of miR-133b on TGFβ1, CTGF, SMA, and COL1A1 expression levels in rabbit corneal fibroblasts. Invest Ophthalmol Vis Sci. 2013 54(10):6944-51.
  • Robison PM, Smith TS, Patel D, Dave M, Lewin A, Pi L, Scott EW, Tuli SS, and Schultz GS. Proteolytic processing of connective tissue growth factor in normal ocular tissues and during corneal wound healing. Invest Ophthalmol Vis Sci. 2012 13;53(13):8093-103.
  • Pi L, Shenoy AK, Liu J, Kim S, Nelson N, Xia H, Hauswirth WW, Petersen BE, Schultz GS, Scott EW. CCN2/CTGF regulates neovessel formation via targeting structurally conserved cystine knot motifs in multiple angiogenic regulators. FASEB J. 2012 26(8):3365-79.
  • Pi L, Xia H, Liu J, Shenoy A, Hauswirth W, Scott E. Roles for connective tissue growth factor in retinal vasculature during development and ischemia. Invest Ophthalmol Vis Sci. 2011 7:52(12):8710-10.
  • Shenoy AK, Butterworth EA, Fisher R, Pi L, Chang L, Appelman HD, Chang M, Scott EW, Huang EH. Colitics-to cancer transition: Wnt activity confers sustained tumor-initiating potential on human precursor-colon cancer stem cells. Cancer Research. 2012 72(19):5091-100.
  • Pi L, Ding XD, Jorgensen M, Pan JJ, Oh S, Pintilie D, Brown A, Song WY, Petersen BE. Connective tissue growth factor with a novel fibronectin binding site promotes cell adhesion and migration during rat oval cell activation. Hepatology. 2008 47(3):996-1004.
  • Oh SH, Witek RP, Bae SH, Darwiche H, Jung Y, Pi L, Brown A, Petersen BE. Detection of transketolase in bone marrow-derived insulin producing cells: benfotiamine enhances insulin synthesis and glucose metabolism. Stem Cells Dev. 2008 18(1):37-46.
  • Pi L, Oh SH, Shupe T, Petersen BE. Connective tissue growth factor is expressed in Thy1+ oval cells and is required for liver regeneration following 2-acetylaminofluorene / partial hepatectomy in rats. Gastroenstrology. 2005. 128(7):2077-2088.
  • Fujikawa T, Oh SH, Pi L, Hatch HM, Shupe T, Petersen BE. Teratoma formation leads to failure of treatment for type I diabetes using embryonic stem cell-derived insulin-producing cells. Am J Pathol. 2005. 166(6):1781-91.
  • Petersen BE, Grossbard B, Hatch H, Pi L, Deng J, Scott EW. Mouse A6-positive hepatic oval cells also express several hematopoietic stem cell markers. Hepatology. 2003. 37(3):632-40.

Selective Abstracts and Oral Presentation at Meetings

  • Pi L Distinct mechanisms of ASH and NASH-associated HCC in diabetic mice. RSA conference 2021 June, Virtual Meeting (Poster presentation)
  • Pi L Regeneration and fibrosis: a balancing act in chronic liver disease and cancer development. Grand rounds in Pathology Department at Tulane University. 2020 November, Louisiana New Orleans (Invited Talk)
  • Pi L Regeneration and fibrosis: a balancing act in fatty liver disease and cancer development. Grand rounds in Pathology Department at University of Florida Gainesville. 2020 October, Florida (Invited Talk)
  • Pi L Targeting Yes-Associated Protein and Connective Tissue Growth Factor Against Liver Cancer Development. Targeted Therapeutics Working Group in UF HCC. 2020 April, Florida (Invited Talk)
  • Pi L Connective Tissue Growth Factor and Its Signaling Partners During Liver Regeneration and Hepatic Progenitor Cell Activation. Workshop On The CCN Family of Genes. 2019 October, Canada Niagara (Oral Presentation)
  • Pi L Ethanol Metabolism and Liver Regeneration: A New Connection in the Regulation of Yes-Associated Protein During Hepatocyte Damage. Experimental Biology Conference 2019 April, Florida Orlando (Oral presentation)
  • Pi L Roles of the YAP/CTGF Signaling Axis in Liver Regeneration, Liver Fibrosis, and Cancer Development. UFHCC TOPICS IN CANCER SEMINAR SERIES 2019 March, Florida Gainesville (Invited Talk)
  • Pi L CTGF Regulation During Liver Regeneration: Involving YAP Activities That Are Antagonized by HNF4a And Required For Ethanol-Detoxification. Gordon Research Conference-Alcohol induced End Organ Diseases (GRS) 2019 March, California Venture (Oral presentation)
  • Pi L. Connective tissue growth factor and a disintegrin and metalloprotease with thrombospondin motifs-7: a pair of substrate and protease critical for hepatic progenitor cell activation and alcohol induced liver injury. 7th World Congress on Molecular Pathology. 2016 July, Australia Melbourne (Oral presentation)
  • Pi L. A disintegrin and metalloprotease with thrombospondin type I motif 7: a new protease for CTGF in hepatic progenitor/oval cell niche. 39th Annual RSA Scientific Meeting. 2016 June, Louisiana New Orleans (Oral presentation)
  • Pi L. Connective tissue growth factor and its regulation during nonalcoholic steatohepatitis and liver cancer development. Research Day, Department of Pediatrics, 2016 June, Florida Gainesville (Oral presentation)
  • Pi L, Jorgensen M, Oh SH, Protopapadakis Y, Gjymishka A, Brown A, Robinson P, Liu C, Scott EW, Schultz GS, and Petersen BE. A disintegrin and metalloprotease with thrombospondin type i motif 7: a new protease for connective tissue growth factor in hepatic progenitor/oval cell niche. Research Day, Department of Pediatrics, 2015 April, Florida Gainesville (Oral presentation)
  • Pi L, Liu C, Scott EW, and Schultz G, and Petersen BE. Connective tissue growth factor and integrin αvβ6: a new pair of regulators critical for ductular reaction and biliary fibrosis. FASEB Summer Research Conference, 2014 July, Keystone, Colorado (Invited Oral presentation)
  • Pi L, Jorgensen M, Scott EW, and Schultz G, and Petersen BE.. Roles of connective tissue growth factor and integrin αvβ6 in ductular reaction and biliary fibrosis. Research Day, Department of Pediatrics, 2014 April, Gainesville, Florida (Oral presentation)