application) The broad, long-term goal of this research is to develop strategies for the prevention and treatment of liver cirrhosis. Towards this goal, the applicant has focused on elucidating the molecular signals that regulate the function of hepatic stellate cells, a key participant in the development of cirrhosis. The central hypothesis of the applicant's research, based in part on his preliminary results, is that contractile force generation, directed migration and proliferation by stellate cells are coordinately regulated by rho, calcium, and protein kinase C signal transduction pathways. To begin to test this hypothesis, the specific aims of this R03 proposal are to: 1) characterize the signals that control contractile force generation by hepatic stellate cells (HSC), and 2) elucidate the signals that regulate directed migration by HSC.
The specific aims will be accomplished using novel assays, established by the applicant, for direct quantitation of contraction and high-resolution visualization of migration to study culture-activated and immortalized stellate cells. Pharmacological and molecular agents will be employed to target critical elements in the rho, calcium and protein kinase C (PKC) signaling pathways to assess their relative contributions to contractile force generation and directed migration by stellate cells. These studies represent requisite steps towards understanding the liver's response to injury and the pathophysiology of cirrhosis. Funding of this award would facilitate completion of the specific aims and greatly enhance the K08 recipient's development into a fully independent investigator capable of obtaining an individual research project grant, R01.
