The goal of this Mentored Scientist Award (K01) application is to promote the development of the applicant into a multi-disciplinarily trained independent principal investigator. The strengths of the application are brought together by three major areas of emphasis as follows. 1) Credentials of the applicant. Dr. Pi's application builds upon her previous track-record of productivity with a concentrated determination to establish scientific independence through a change in research direction. The applicant's short-term goals encompass the acquisition of technical skills, initiation and establishment of an independent line of research, and to enhance professional skills (i.e. scientific writing, mentorin of trainees, grant writing, oral communication). Long-term goals are centered on becoming a leader in regenerative medicine, achieving a tenure-track position, training future scientists, and involvement in society and faculty leadership. 2) Training environment. Dr. Pi has received full commitment and the support of Drs. Bryon Petersen (mentor) and Gregory Schultz (co-mentor) to implement and complete the training necessary to advance outstanding junior faculty. Dr. Petersen is recognized as a world leader in the fields of stem cell biology and liver regeneration. Dr. Schultz complements the candidate's new direction of research by bringing renowned experience of understanding mechanism of fibrotic disorders. Dr. Pi has selected Drs. Lewin, Srivastava, and Gao as additional members due to their remarkable commitment and experience in developing the next generation of successful academic scientists. Dr. Pi will use the results obtained during the award period to justify and extend the scope of the project by formulating an independent New Investigator R01 application to advance into a tenure track position in academia. 3). Innovative models and research. The central hypothesis to be tested is that: Connective tissue growth factor (CTGF) is an important therapeutic target for alcoholic liver disease (ALD). The spectrum of ALD encompasses steatohepatitis, fibrosis to end-stage cirrhosis and liver cancer. The goal of this proposal is to understand the molecular mechanism of ALD and identify therapeutic targets that reverse alcoholic fibrosis and prevent cirrhosis. So far, there is no FDA approved treatment for any fibrotic disorder. CTGF overexpression, together with transforming growth factor (TGF)-, has been found in various kinds of fibrotic disorders. Our research has identified CTGF as a key molecule in the regulation of liver repair and hepatic progenitor cell (HPC) activation. We have developed several genetic mouse tools and will use them to determine the function of CTGF in ALD by testing: 1) whether CTGF can potentiate hepatocyte injury and inflammation during the early phase of alcoholic liver injury; 2) whether CTGF plays an important role in progression of alcoholic fibrosis and HPC activation; 3) whether targeting CTGF and TGF- utilizing RNA interference and adeno- associated virus (AAV) delivery system reduces alcoholic fibrosis. This project will employ a multidisciplinary approach, including liver pathophysiology, AAV and RNA-based therapies to test the central hypothesis.
Alcoholic liver disease is a major health and financial concern worldwide. This project focuses on the roles of connective tissue growth factor in ALD and tests whether this pro-fibrogenic factor is a viable therapeutic target for reversing disease progression. A better understanding of the molecular basis of alcoholic liver disease could impact the millions of Americans afflicted with this problem.
