Portal hypertension and its complications account for much of the morbidity and mortality associated with cirrhosis. The long-term goal of our lab is to understand the molecular control mechanisms of portal hypertension. Sinusoidal vasoconstriction is an essential component in the development of portal hypertension and occurs through contraction of hepatic stellate cells (HSC). However, the process by which these contractile HSC organize and wrap around the sinusoidal channel in cirrhosis, is enigmatic. Our studies have focused on migration signals in HSC that contribute to this process of "sinusoidal remodeling". Our exciting preliminary data demonstrates that 1) the small GTPase Rac and the actin-binding protein, VASP, promote HSC migration by generating finger-like filopodia from the plasma membrane, 2) Ableson tyrosine kinase (c- abl) promotes HSC-mediated formation of vascular tubes in vitro, 3) the multifunctional cytokine, nitric oxide (NO) inhibits filopodia formation and HSC-driven vascular tube formation through a protein kinase G (PKG)- dependent pathway, and 4) defects in migration signaling in HSC from animal models of portal hypertension are associated with increased sinusoidal coverage by HSC and an ensuing increase in portal pressure, pointing to an in vivo relevance of the proposed pathways. We have parlayed these novel findings into the central hypothesis that;Rac, acting in tandem with its regulatory partners, VASP and c-abl, maintains a molecular counterbalance with NO that governs the formation of membrane filopodia and HSC-driven vascular tubes. Alterations in this counterbalance influence portal pressure by regulating the level of coverage of the sinusoids by contractile HSC.
The Specific Aims of the proposal are to test the three subhypotheses that: 1) Rac dependent filopodia formation in HSC is inhibited by NO through PKG dependent inactivation of the Rac effector protein, VASP, 2) C-abl governs HSC-driven vascular tube formation through pathways regulated by Rac and NO, and which are augmented in portal hypertension, and 3) the counterbalance of Rac and NO in HSC regulates sinusoidal remodeling and portal hypertension in vivo. Thus, this proposal will use state-of-the- art methodologies and world-renown collaborators, to elucidate novel signaling pathways in HSC that contribute to portal hypertension, which in turn will set a trajectory towards new therapeutic approaches towards portal hypertension and its symptoms.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK059615-10
Application #
8294734
Study Section
Special Emphasis Panel (ZRG1-DIG-C (02))
Program Officer
Sherker, Averell H
Project Start
2001-04-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
10
Fiscal Year
2012
Total Cost
$314,697
Indirect Cost
$106,426
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Simonetto, Douglas A; Yang, Hui-yin; Yin, Meng et al. (2015) Chronic passive venous congestion drives hepatic fibrogenesis via sinusoidal thrombosis and mechanical forces. Hepatology 61:648-59
Liu, Chunsheng; Li, Jiachu; Xiang, Xiaoyu et al. (2014) PDGF receptor-? promotes TGF-? signaling in hepatic stellate cells via transcriptional and posttranscriptional regulation of TGF-? receptors. Am J Physiol Gastrointest Liver Physiol 307:G749-59
Iwakiri, Yasuko; Shah, Vijay; Rockey, Don C (2014) Vascular pathobiology in chronic liver disease and cirrhosis - current status and future directions. J Hepatol 61:912-24
Yang, Liu; Kwon, Junghee; Popov, Yury et al. (2014) Vascular endothelial growth factor promotes fibrosis resolution and repair in mice. Gastroenterology 146:1339-50.e1
Liu, Chunsheng; Billadeau, Daniel D; Abdelhakim, Haitham et al. (2013) IQGAP1 suppresses T*RII-mediated myofibroblastic activation and metastatic growth in liver. J Clin Invest 123:1138-56
Zhu, Qiang; Zou, Li; Jagavelu, Kumaravelu et al. (2012) Intestinal decontamination inhibits TLR4 dependent fibronectin-mediated cross-talk between stellate cells and endothelial cells in liver fibrosis in mice. J Hepatol 56:893-9
Zhang, Chunqing; Thabut, Dominique; Kamath, Patrick S et al. (2011) Oesophageal varices in cirrhotic patients: from variceal screening to primary prophylaxis of the first oesophageal variceal bleeding. Liver Int 31:108-19
Vaa, Brianna E; Asrani, Sumeet K; Dunn, Winston et al. (2011) Influence of serum sodium on MELD-based survival prediction in alcoholic hepatitis. Mayo Clin Proc 86:37-42
Thabut, Dominique; Routray, Chittaranjan; Lomberk, Gwen et al. (2011) Complementary vascular and matrix regulatory pathways underlie the beneficial mechanism of action of sorafenib in liver fibrosis. Hepatology 54:573-85
Jagavelu, Kumaravelu; Routray, Chittaranjan; Shergill, Uday et al. (2010) Endothelial cell toll-like receptor 4 regulates fibrosis-associated angiogenesis in the liver. Hepatology 52:590-601

Showing the most recent 10 out of 29 publications