The scientific goal of this proposal is to understand the subcellular signaling pathways involved in growth and timely death of prostate epithelial cells. Androgen deprivation leads to apoptosis of normal and prostate cancer cells. Several lines of evidence support the hypothesis that receptor tyrosine kinase signaling pathways in combination with anti-apoptosis protein protect the prostate cell from death. Our preliminary data androgen-independent growth. We hypothesize that aberrant signaling by receptor tyrosine kinases such as HER-2/neu leads to downstream activation of the mitogen-activated protein kinase (MAPK) pathway and enhanced anti-apoptotic function of bcl-2 family members. The first and second specific aims will explore two branches of the MAPK pathway downstream of HER-2/neu, Raf-1 and MEKK1, and their role in androgen-independent prostate cell growth.
The final aim of this proposal will translate the in vitro work to an in vivo mouse model of prostate development using prostate-specific expression of a HER-2/neu transgene. As a gastroenterologist and scientist, I am interested in studying immune-epithelial interactions in the intestinal mucosa. My research has begun to address the molecular mechanisms involved in intestinal epithelial cell apoptosis in response to lymphocyte-mediated stimuli. I realize, however, that in order to answer the next tier of research questions as an independent investigator, I require additional training. The training most appropriate to complement my previous research experience and to facilitate the transition to independence is in the area of signal transduction. The laboratory of the sponsor uses advanced molecular biologic methods to manipulate signal transduction pathways in epithelial systems. The research proposal outlined in this grant has been carefully chosen for both its scientific merit and the skills required to answer the questions. Although the model system described is the prostate, the approach required to study regulation of apoptosis and growth factor-dependent growth can be applied to other epithelia. In addition to the hands- on laboratory work, I will be taking graduate-level courses in cellular and molecular biology. After this three year period of training, I will return to gastrointestinal research with the support of my co-sponsor and begin to develop intestinal models to study normal and pathologic states of apoptosis.
