The general long term objectives of the proposed research are to attain a detailed understanding of the biochemistry and physiology of sex-hormone-binding globulin (SHBG) and corticosteroid-binding globulin (CBG). These are the proteins in plasma to which all of the physiologically important steroid hormones are bound. Although marked alterations in the concentration of both of these proteins in plasma are known to occur in a variety of human conditions i.e. pregnancy, obesity, thyrotoxicosis, hirsutism, polycystic ovary syndrome, and hepatic cirrhosis, among others, our understanding of these changes are at an early stage. Our approach to the understanding of these two proteins during the coming grant period will be multifaceted. We will study the interaction of CBG with its cell membrane receptors. Our model, will be the rat, and we will examine both the physiochemical nature of the interaction and factors which effect it; the physical and functional properties of the receptor; and the organ distribution of the receptor and its endocrine regulation. An animal model exists in which it is possible to cause marked alterations in hepatic CBG concentration in vivo. We will determine the effects of such manipulations on corticosterone metabolism and glucocorticoid receptor translocation to the nucleus. We will affinity label highly purified human CBG and SHBG, and rat CBG, and, after specific enzymatic hydrolysis of the proteins, sequence the affinity labeled peptides to search for homologies in these 3 related but different steroid binding sites. We will use a human hepatoblastoma cell line in vitro both to study endocrine influences on SHBG secretion, and expand our knowledge of the structure of secreted SHBG and its precursor form.
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