Spatiotemporal Modulation of PIP[3]Signaling in Prostatic Tubulogenesis

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DESCRIPTION (provided by applicant): This proposal describes the five-year career development plan of a physician-scientist with clinical expertise in urologic pathology who is committed to establishing an independent laboratory focusing on prostatic epithelial morphogenesis and migration. She will add to her scientific training with coursework in developmental biology, cellular migration, and cutting-edge live-cell imaging techniques. The research will take place in the Center for Cell Dynamics, a state-of-the-art multidisciplinary center at the Johns Hopkins School of Medicine that brings together experts studying spatially and temporally regulated molecular events in living cells. The proposed research project will focus on elucidating the signaling pathways that drive prostatic epithelial morphogenesis and are potentially re-activated in adult diseases of abnormal prostate growth. This project will bring together the strengths of her two scientific mentors, Dr. Denise Montell, an international expert in the basic science of epithelial cell migration, and Dr. David Berman, a urologic pathologist with a laboratory focused on prostate development and disease. Despite the highly conserved role of PIP3 (phosphatidylinositol [3,4,5]- trisphosphate) signaling in regulating cellular polarity, the role of PIP3 signaling in mammalian epithelial morphogenesis remains unknown. Based on preliminary data, we hypothesize that spatiotemporal modulation of PIP3 signaling is critical for two key processes driving prostatic tubulogenesis: prostatic ductal elongation and apicobasal polarity specification. Taking advantage of a 3D prostate epithelial culture system developed in our laboratory, as well as in vitro prostate organ culture and state-of-the-art time-lapse imaging techniques, we will examine the effects of PIP3 modulation on prostatic epithelial morphogenesis in three inter-related Aims: 1)We will establish the intracellular localization of and requirement for PIP3 signaling during prostatic ductal elongation using mice transgenic for a PIP3 biosensor and isoform-specific PI3K (phosphoinositide-3-kinase) inhibitors; 2)We will define the cellular mechanism by which PIP3 signaling regulates prostatic ductal elongation by examining the specific effects of PI3K inhibition on prostatic epithelial migration, proliferation and apoptosis; 3)We will examine the role of PIP3 in regulating apicobasal polarity by modulating the activity and levels of PI3K and PTEN (phosphatase and tensin homologue) in vitro during acinar morphogenesis and in vivo using a novel transgenic mouse line established in our laboratory. By elucidating the signaling networks that drive prostatic growth during development, we will better understand how dysregulation of these pathways may lead to prostatic disease in the adult. PUBLIC HEALTH RELEVANCE: There is increasing evidence that many of the signaling pathways that regulate prostatic growth during embryonic development are reactivated in adult diseases, such as benign prostatic hyperplasia and cancer. We have preliminary data that suggests the PIP3 signaling pathway is important during prostatic development, and we propose to study how its activation may enable the growth of prostatic epithelial tubules. This pathway is of particular interest because there are numerous drugs available for modulating its activity that may be useful for the treatment of human prostate diseases once we fully understand how the pathway works.