Liver fibrosis is the excessive accumulation of extracellular matrix as a wound healing response to chronic injuries from a broad range of liver diseases, irrespective of the underlying etiology. Advanced liver fibrosis may lead to cirrhosis, liver failure, and neoplasia. Extracellular matrix deposition is crucial to wound healing by promoting tissue formation and integrity, but commonly becomes uncontrolled in chronic injuries and leads to fibrosis. Ductular reaction is part of the injury response in the liver occurring at te interphase of the parenchymal and portal compartments that promotes bile duct regeneration. Although prominent in response to biliary and cholestatic damages, ductular reaction is observed in virtually all chronic human liver diseases. Recent studies have revealed that the matricellular protein CCN1 induces cholangiocyte proliferation and ductular reaction in response to cholestatic injuries through integrin ?v?5-mediated activation of NF?B, leading to Jag1 expression and Jag1/Notch signaling. Furthermore, CCN1 is able to restrict and resolve liver fibrosis induced by either hepatotoxin (carbon tetrachloride) or cholestasis (bile duct ligation) b inducing cellular senescence in myofibroblasts derived from hepatic stellate cells and portal fibroblasts. CCN1 also appears to regulate myofibroblast activation and resolution of inflammation. Based on these observations, we hypothesize that CCN1 serves multiple functions in different stages of hepatobiliary injury repair through binding distinct integrins in different cell types. We will scrutinize this hypothesis in three specific aims: (1) to conduct genetic and functional analyses of the heretofore unexplored CCN1-?v?5-NF?B axis in ductular reaction; (2) to examine how CCN1 induces the reactive cholangiocyte phenotype and differentiation of hepatic progenitor cells in the ductular reaction niche; and (3) to investigate how CCN1 regulates the initiation and termination of fibrogenesis in injury repair. These studies will elucidate the diverse roles of CCN1 as a critical regulator of injury repair in chronic liver diseases, and may lead to new therapeutic targets and treatment strategies for the prevention and treatment of liver fibrosis.

Public Health Relevance

Liver fibrosis is a result of sustained wound healing response to chronic injuries from such diverse causes as viral infections, alcoholism, and non-alcoholic fatty liver disease, and can progress to cirrhosis in which serious and live-threatening complications may arise. This proposal seeks to understand the biologically programmed healing mechanism in the liver for injury repair, which may be harnessed to help control and ameliorate fibrotic pathologies. We anticipate that results from these studies will reveal novel targets of therapies and prompt therapeutic strategies that may both promote liver injury repair and reduce the risk of liver fibrosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM078492-12
Application #
9502979
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Somers, Scott D
Project Start
2007-08-09
Project End
2019-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
12
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Illinois at Chicago
Department
Biochemistry
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
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Jun, Joon-Il; Lau, Lester F (2018) Resolution of organ fibrosis. J Clin Invest 128:97-107
Vaidya, Ruben; Zambrano, Ronald; Hummler, Julia K et al. (2017) Recombinant CCN1 prevents hyperoxia-induced lung injury in neonatal rats. Pediatr Res 82:863-871
Lee, Sangmi; Elaskandrany, Menna; Lau, Lester F et al. (2017) Interplay between CCN1 and Wnt5a in endothelial cells and pericytes determines the angiogenic outcome in a model of ischemic retinopathy. Sci Rep 7:1405
Monzon, Ricardo I; Kim, Ki-Hyun; Lau, Lester F (2017) Construction and Analysis of an Allelic Series of Ccn1 Knockin Mice. Methods Mol Biol 1489:361-376
Lau, Lester F (2016) Cell surface receptors for CCN proteins. J Cell Commun Signal 10:121-7
Chen, C-C; Kim, K-H; Lau, L F (2016) The matricellular protein CCN1 suppresses hepatocarcinogenesis by inhibiting compensatory proliferation. Oncogene 35:1314-23
Kim, Ki-Hyun; Chen, Chih-Chiun; Alpini, Gianfranco et al. (2015) CCN1 induces hepatic ductular reaction through integrin ?v??-mediated activation of NF-?B. J Clin Invest 125:1886-900
Chintala, Hemabindu; Krupska, Izabela; Yan, Lulu et al. (2015) The matricellular protein CCN1 controls retinal angiogenesis by targeting VEGF, Src homology 2 domain phosphatase-1 and Notch signaling. Development 142:2364-74
Jun, Joon-Il; Kim, Ki-Hyun; Lau, Lester F (2015) The matricellular protein CCN1 mediates neutrophil efferocytosis in cutaneous wound healing. Nat Commun 6:7386

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