This is a revised application for funds to support a Program Project Grant at the Oregon Health Sciences University School of Medicine. All projects have been rewritten according to the comments of the site visit review team. The Program is now composed of 5 interwoven projects designed to test the hypothesis that the Renin Angiotensin System (RAS) is a powerful signalling mechanisms that regulates many facets of maternal physiology during pregnancy and development of the embryo, fetus, and newborn. Project 1 will investigate alterations of the RAS in the offspring of protein deprived rats during pregnancy that may explain the propensity for such offspring to be hypertensive later in life. Project 2 will investigate the role of the RAS in regulating fetal water acquisition and in the causation of hydrops fetalis in sheep. Project 3 will determine the separate roles of Ang II asn a receptor mediated promoter of myocyte growth and differentiation and regulator of systolic hemodynamic load in the sheep fetus. Project 4 will test the hypothesis that the mitogenic responses of porcine vascular smooth muscle cells to a Ang II are altered as maturation proceeds and that the late cycle maturationprocess is dependent on the expression of specific growth factor systems. Project 5 will investigate the role of Ang II in stimulating the mitogen activated protein kinase cascade in young and adult rats that leads to early gene expression and regulation of cell division and differentiation. 9001 is an animal core, headed by a veterinarian who will oversee animal purchase and use and will provide overall cos savings. 9002 is an imaging core headed by the director of the OHSU histopathology laboratories, and will provide immunochemistry and in situ hybridization services. These projects have attracted a highly talented interdisciplinary faculty and are designed to use the integrated tools of whole animal physiology, cell culture and molecular biology to address problems of high priority in human development
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