Portal hypertension accounts for significant morbidity and mortality in patients with liver cirrhosis although the precise events that mediate this syndrome remain incompletely understood. The Overall Objective of this grant is to define the molecular mechanisms within the hepatic sinusoids that are responsible for portal hypertension with the goal of eventually developing new therapeutic approaches that can be tested in humans. Paracrine interactions between liver endothelial cells (LEC) and hepatic stellate cells (HSC) are required for sinusoidal vascular remodeling and contraction, which are critical steps in portal hypertension. In this regard our Preliminary Data shows that 1) LEC generate the lipid signaling molecule sphingosine-1 phosphate (S1P) which promotes HSC migration and contraction, 2) stimulation of the angiogenic growth factor receptor, fibroblast growth factor receptor 1 (FGFR) in LEC by FGF2 and FGF21 leads to S1P production, and 3) pharmacologic inhibition of LEC growth factor pathways attenuates portal hypertension development in vivo. We have parlayed these novel findings into the Central Hypothesis of the current proposal;that FGFR activation in LEC increases S1P production which stimulates HSC recruitment and contraction of hepatic sinusoids leading to portal hypertension.
The Aims are to test the sub-hypotheses that: 1) LEC recruit and contract HSC through increased production and cellular release of S1P.
Aim 1 a will examine how both exosome and paracrine release of S1P from LEC stimulates HSC recruitment and contraction, respectively.
Aim 1 b will discern how FGFR signaling transcriptionally activates the S1P generating enzyme, sphingosine kinase 1 (SK1) through an epigenetic mechanism of chromatin regulation. 2) Activation of S1P production from LEC occurs through FGFR phosphorylation by FGF21 and ensuing endosome based signaling.
Aim 2 a will explore new mechanisms by which the endocrine FGF family member, FGF21 regulates phosphorylation of specific FGFR residues to activate FGFR signaling and S1P production.
Aim 2 b will focus on how FGF21 promotes FGFR internalization into intracellular endosomes to govern FGFR signaling and S1P production. 3) Inhibition of FGFR-S1P signaling in LEC attenuates development of portal hypertension in vivo by blocking recruitment and contraction of HSC.
Aim 3 a will dissect how the angiogenic FGFR pathway contributes to portal hypertension using a unique FGF delivery system in mice with genetic deletion of FGFR from LEC.
Aim 3 b will uncover the role of S1P in portal hypertension using an innovative exosome-transfer technique in mice harboring a genetic defect in S1P production.
Aim 3 c will test the role of FGFR internalization on portal hypertension development in vivo using a new mouse line that we recently derived. Thus this proposal will utilize a variety of innovative yet feasible, cell and molecular approaches, both in vitro and in vivo to elucidate novel pathways that contribute to portal hypertension. The results, by advancing our understanding of sinusoidal structure and function, will set a trajectory towards new and significant advances to treat portal hypertension in humans.

Public Health Relevance

Portal hypertension is the major cause of morbidity and mortality in patients with cirrhosis. This work is focused on developing new molecular targets for portal hypertension and also testing new therapies preclinically. Thus, it has the potential to lea to new treatments for humans suffering from this syndrome.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01DK059615-11A1
Application #
8753742
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Sherker, Averell H
Project Start
Project End
Budget Start
Budget End
Support Year
11
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
City
Rochester
State
MN
Country
United States
Zip Code
55905
Hirsova, Petra; Ibrahim, Samar H; Krishnan, Anuradha et al. (2016) Lipid-Induced Signaling Causes Release of Inflammatory Extracellular Vesicles From Hepatocytes. Gastroenterology 150:956-67
Nagy, Laura E; Ding, Wen-Xing; Cresci, Gail et al. (2016) Linking Pathogenic Mechanisms of Alcoholic Liver Disease With Clinical Phenotypes. Gastroenterology 150:1756-68
Johnson, Matthew L; Distelmaier, Klaus; Lanza, Ian R et al. (2016) Mechanism by Which Caloric Restriction Improves Insulin Sensitivity in Sedentary Obese Adults. Diabetes 65:74-84
Verma, Vikas K; Li, Haiyang; Wang, Ruisi et al. (2016) Alcohol stimulates macrophage activation through caspase-dependent hepatocyte derived release of CD40L containing extracellular vesicles. J Hepatol 64:651-60
Marrone, Giusi; Shah, Vijay H; Gracia-Sancho, Jordi (2016) Sinusoidal communication in liver fibrosis and regeneration. J Hepatol 65:608-17
Hirsova, Petra; Ibrahim, Samar H; Verma, Vikas K et al. (2016) Extracellular vesicles in liver pathobiology: Small particles with big impact. Hepatology 64:2219-2233
Lalia, Antigoni Z; Dasari, Surendra; Johnson, Matthew L et al. (2016) Predictors of Whole-Body Insulin Sensitivity Across Ages and Adiposity in Adult Humans. J Clin Endocrinol Metab 101:626-34
Johnson, Matthew L; Irving, Brian A; Lanza, Ian R et al. (2015) Differential Effect of Endurance Training on Mitochondrial Protein Damage, Degradation, and Acetylation in the Context of Aging. J Gerontol A Biol Sci Med Sci 70:1386-93
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
Kamath, Patrick S; Therneau, Terry; Shah, Vijay H (2015) MELDing the Lille Score to More Accurately Predict Mortality in Alcoholic Hepatitis. Gastroenterology 149:281-3

Showing the most recent 10 out of 56 publications