Regulation of Stellate Cell Contractility

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DESCRIPTION (provided by applicant): The wound healing response to liver injury is characterized by enhanced fibrogenesis as well as tissue contraction. The clinical result, cirrhosis, is a major cause of morbidity and mortality in the United States and worldwide. It has recently been established that resident hepatic mesenchymal cells, termed perisinusoidal stellate cells (Ito cells or lipocytes), play a critical role in the hepatic wounding response. One of the key events in this process is the "activation" of stellate cells, resulting in increased extracellular matrix synthesis and de novo smooth muscle (-actin expression, and recently smooth muscle myosin isoforms. Expression of smooth muscle proteins in stellate cells has been coupled to their potential for enhanced contractility. Further, it is postulated that the highly contractile phenotype found in activated stellate cells has important physiologic effects in the injured liver by contributing to increased intrahepatic resistance to blood flow typical of portal hypertension and perhaps by physical distortion of the liver. In preliminary studies presented in this proposal, it is shown that smooth muscle g- actin directly mediates stellate cell contraction and that it plays an important physiologic role in mediating portal hypertension. Further, preliminary data presented in the application indicate that myosin motors are upregulated during the injury and activation process, providing a putative molecular mechanism for enhanced contractility characteristic of activated stellate cells. The overall aim of the proposal is therefore to understand the molecular basis for enhanced contractility typical of activated stellate cells and to determine whether interruption of this exaggerated contractile phenotype has effects on intrahepatic portal hypertension or the wound healing response itself. Toward this end, the application proposes to examine myosin II regulation and the myosin signaling pathway in normal and activated stellate cells Subsequent studies will explore mechanisms of smooth muscle protein (i.e., smooth muscle myosin and actin) regulation as well as the in vivo function of each of these proteins in the liver. Physiologic endpoints will be an important focus. The proposed studies will shed light on the molecular basis of stellate cell contractility and moreover have direct relevance to human liver disease.