Hepatic stellate cells (also called Ito cells or lipocytes) modulate the liver's response to chronic injury. When the liver is injured, stellate cells undergo a phenotypic change, termed activation, characterized by fibrogenesis, proliferation, and contractility. emerging evidence indicates that the contractile behavior of activated stellate cells contributes to the development of portal hypertension. Despite extensive study, the processes coupling extracellular stimuli to stellate cell contraction are poorly understood. Preliminary results indicate that calcium ion (Ca2+) and small monomeric GTPase (i.e., Rho) signaling pathways link endothelin 1 (ET-1) to stellate cell contraction. The immediate goal of this project is to test the working hypothesis, based on these findings, that Ca2+ and Rho signaling pathways coordinately couple ET-1 to stellate cell contraction. therefore, the specific aims of this proposal are to: 1) Determine the relative contributions of Ca2+ and Rho signaling pathwa7ys to stellate cell contraction. 2) Characterize ET-1 modulated Ca2+ permeable channels in stellate cells. 3) Define the role of myosin regulatory light chain phosphorylation in Rho-stimulated stellate cell contraction. A multi-pronged approach will be employed to achieve these specific aims, taking advantage of methods acquired funding the candidates training (i.e, patch clamp, molecular biology), and new skills that will be learned as part of his career development plan (i.e, cellular imaging, protein biochemistry). This proposal incorporates the candidate's long-standing interest in stimulus-contraction coupling with his clinical focus on liver disease. These studies will improve our understanding of the mechanisms underlying portal hypertension, and facilitate the development of novel agents for the treatment of t his serious health problem.
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