Pyk2 Signaling In Intestinal Epithelial Cells

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DESCRIPTION (provided by applicant): My long-term goal is to achieve an academic career in medicine, continue to teach, and to establish an independent program of research in the field of gastrointestinal signal transduction. At the same time, I wish to continue in the practice of clinical medicine, and ultimately to contribute to the advancement of basic research as it relates to health. In particular, though my work analyzes molecular mechanisms of cell signaling, I aim to study these with an eye towards developmental processes, such as intestinal growth and maturation, or towards issues important to both adult and child populations, such as inflammatory bowel disease. My more immediate priority is to obtain grant support in order to continue both my research and my growth as a scientist. I seek an environment for my initial junior faculty position that will provide me with both a depth of resources to stimulate scientific growth, and a strong commitment to protected research time. I have chosen UCLA and my mentor, Dr. Enrique Rozengurt, because of his expertise in the field of signal transduction, the resources of the university, and the commitment of Dr. Rozengurt and of the Department of Pediatrics to support my training. This research proposal focuses on understanding the mechanisms by which environmental signals are translated into cellular functions in intestinal epithelia. Intestinal epithelial cell functions, including growth, migration, and differentiation, are regulated by a wide variety of soluble and contact-dependent stimuli. The IEC-6 and IEC-18 small intestinal epithelial cell lines have been widely used as models of proliferation and wound restitution. Specifically, we aim to study signaling pathways in the response to G protein-coupled receptor (GPCR) agonists. The central hypothesis we will address is that the cytoplasmic tyrosine kinase Pyk2 acts to integrate multiple signals in intestinal epithelial cells and plays a key role in mediating their cellular effects. Our first specific aim is to study the regulation of Pyk2 by phosphorylation at distinct sites, and by interactions with other signaling proteins, following stimulation of GPCR signaling. Our second aim is to correlate Pyk2 activity to cytoskeletal structure and function. The third aim is to evaluate the role of Pyk2 in regulating DNA synthesis and cell motility. By elucidating key signal transduction pathways in the intestinal epithelium, we will better understand the mechanisms underlying the processes of growth, wound healing, and neoplasia in the GI epithelium.