Maldevelopment of the kidney and urinary tract accounts for approximately 30% of renal failure in children. A delineation and understanding of the molecular basis of renal organogenesis is necessary for development of strategies for treatment and prevention of these disorders. The formation of all organs during embryogenesis, including kidney, is dependent upon the timed and sequential expression of a number of polypeptide growth factors. The goals of the present proposal are to characterize the expression of these agents in the developing metanephros, to define the roles of growth factors working alone or in concert with one another in embryonic kidney development, and to provide insight into the role of the Wilms' tumor gene locus in the regulation of metanephric growth factor expression. To these ends we will utilize metanephroi surgically dissected from rat embryos at different stages of metanephrogenesis and metanephroi dissected from embryos at the initiation of organogenesis and grown in organ culture. Our investigations will utilize a number of cellular and molecular biological technologies to characterize the sequence of polypeptide growth factor gene expression and growth factor activities in the developing metanephric kidney, their role(s) in metanephrogenesis and whether their productions are regulated by a gene equivalent to the human Wilms' tumor locus. In a broad sense, these investigations will catalog the synthesis and functions of several polypeptide growth factors in a developing organ system. More specifically, in view of what is already known about the metanephrogenic process, our studies will provide important insights into the molecular regulation of renal development and into the cellular and molecular pathophysiologies that underlie abnormalities in kidney formation including the malignant transformation of Wilms' tumor.
Showing the most recent 10 out of 82 publications
