The research projects proposed here are closely interrelated and have evolved from past research productivity and collaboration. The common aim of the six research units (4 cores) is to expand our knowledge of the neuroendocrine-metabolic regulation of reproductive function and its disorders in women. Cellular, biochemical and genomic mechanisms will be explored through the use of a variety of in vitro and in vivo techniques, in which both animal and human tissue and cells will be employed. Animal experimentation will be conducted for those studies which are not feasible with human subjects such as the molecular analysis of the regulation of the follicle-stimulating hormone beta-subunit gene (Mellon, Unit 2), and factors controlling follicular atresia (Erickson, Unit 3). Parallel studies in animal and human tissues with or without prior in vivo treatments will be conducted to define the paracrine/autocrine function of inhibin-related peptides. The strategy for the investigation in humans is to circumvent the inherent limitations by selecting disease states to serve as """"""""nature made"""""""" experiments and to provide a compliment to physiological studies in normal human subjects and the laboratory based experiments in animals. Studies of neuroendocrine-metabolic control of the human menstrual cycle will be focused on conditions with aberrations of the link between the brain and ovary and between peripheral metabolic disorders and the reproductive axis such as functional hypothalamic amenorrhea and polycystic ovary syndrome (Yen, Unit 1). The cellular mechanisms of insulin resistance and tissue specificity, particularly the postreceptor defects as they relate to hyperinsulinemic chronic anovulation of polycystic ovary syndrome will be defined (Olefsky/Ciraraldi, Unit 5). Finally, multiple interactions and collaborations between and among units and cores are planned. This attribute of our Center can be exemplified by the attempt to clone human GnRH receptor CDNA (Unit 1) followed by binding, expression and regulation studies using RNA derived from the gonadotrope cell line and dispersed human pituitary cells Core C-Unit 1). The participants in this proposed research Center have been selected not only because of the commonality of their interests but also because of their acknowledged expertise in their respective fields.
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