Our long range goal is to elucidate the structures and understand the roles of individual human growth hormone (hGH) variant sin the regulation of human physiology in health and disease states. As our next objective in pursuit of this goal, we propose in this application to investigate the structure and biological roles of a newly identified hGH variant: mercaptoethanol-resistant (MER) 45 kDa hGH. Due to its novelty, there exists a gap in our knowledge regarding its structure and biological actions. The central hypothesis of the application is that structural components that make MER 45 kDa hGH different from the 22 kDa hGH also make its biological activities different from that of 22 kDa HGH. The rationale behind the proposed research centers on the fact that structural variants of GH and prolactin that have recently been studied possess biological activities that differ from those of their respective major isoforms. To test the hypothesis, this research plan will focus on ascertaining the structure and biological activities of MER 45 kDa HGH. Both the prolactin-like and GH-like properties of MER 45 kDa hGH will be assessed in a set of representative in vitro and in vivo bioassays. The specific objectives are: 1) To determine the structure of MER 45 kDa hGH; 2) To determine the biological potencies of MER 45 kDa hGH in a range of biological assays that are measures of GH action; 3) To correlate the structure of MER 45 kDa hGH to its biological functions; 4) To generate anti-MER 45 kDa hGH monoclonal antibodies for use in development of an isoform-specific immunoassay that will be an important tool in discerning its physiological regulation. At the conclusion of this research, we expect to have determined the structure of MER 45 kDa hGH, elucidate its physiological significance, ascertained it structure-activity relationships and developed an isoform- specific immunoassay The new information gained from the research of the present proposal will fill the gap in our current understanding of the structure-function relationships of MER 45 kDa hGH. New therapeutic strategies could result from these investigations.
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