Humoral factors interact with nutrient supply to determine how nutrients affect statural growth, tissue repair and tissue maintenance. The actions of growth hormone (GH), an important hormonal stimulator of generalized growth, are moderated by nutrient supply. During fasting or when the intake of dietary energy or protein is limited, the growth-promoting (anabolic) actions of GH are attenuated. Because the primary mechanism by which GH promotes growth is the stimulation of Insulin-like Growth Factor I (IGF-I), study of IGF-1 biosynthesis is central to understanding how GH regulates growth and how nutrition modulates GH responses, IGF-I and growth. This application proposes to examine the role of nutrient intake of the major steps in the cascade of events that result in GH and IGF-stimulated tissue growth. Specific points in the cascade will be examined by experiments intended to determine: the effects of nutrient on GH receptors in cells and on the abundance of messenger RNA (mRNA) for the GH receptor in various tissues; the precise mechanisms whereby the mRNA for IGF-1 and IGF binding proteins are decreased during fasting and during dietary protein restriction; whether ingestion of food produces direct stimulation of IGF-1 synthesis in gut, independent of growth in other tissues; the role of dietary carbohydrate in regulating IGF-1 and growth, and to discover how carbohydrate restriction produces these effects. The applicants also propose to test the capacity of IGF-1 to promote growth directly when nutrient intake is restricted. This will help clarify whether the effects of nutrition on growth are mediated by decreased IGF-1 or by attenuation of the effects IGF-1. Finally, they propose to begin studies in human volunteers of the mechanisms by which nutrient intake regulates the expression of IGF-1 mRNA. Gaining a clearer understanding of the relationship of nutrient intake, growth factors and growth should provide greater insight into the events that occur when humans are made catabolic by acute or chronic disease or as a result of surgery. Having this information should permit the development of new therapies or improvements in existing treatments that might attenuate catabolism, promote anabolism and hasten recovery from disease.
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