The objective of this application is to provide a five-year training program for the development of an academic career in molecular endocrinology. The applicant proposes to implement a research program studying the the role of nutrition in the central reproductive axis, thus building on scientific skills acquired during fellowship training. The long-term objective is to provide the applicant with the guidance and expertise necessary to design and implement a basic and translational research program that will lead to better care of patients with endocrine disorders. This program, supported by the Baltimore-Chicago Center for Reproductive Research (U54 HD41859), will be mentored by Dr. Fredric Wondisford, director of the Division of Metabolism at the Johns Hopkins University School of Medicine. The proposed research will focus on the role and mechanisms of insulin and growth factor signaling in the central reproductive axis at the level of the pituitary. Disruption of insulin and growth factor signaling in the reproductive axis has been shown to severely impair reproductive function in experimental animals. However, studies to date have not differentiated between effects of perturbed signaling in the hypothalamus versus the pituitary. Experiments outlined in this proposal will utilize model cell lines and mouse models of loss of insulin and insulin-like growth factor 1 (IGF-1) signaling in the pituitary gonadotroph.
Specific aims are to: (1) Determine the role of insulin and IGF-1 signaling in the pituitary gonadotroph utilizing conditional knockout mice. (2) Characterize mechanisms of insulin and IGF-1 signaling on gonadotroph-specific gene expression via Egr-1 and CREB-binding protein (CBP). The role of CBP in insulin and IGF-1-mediated LH expression will be determined via luciferase reporter assays, gene knockdown experiments, and assays to determine CBP binding to the LH-beta promoter. 3) Characterize the state of insulin sensitivity in gonadotrophs in a model of obesity-related infertility and insulin resistance. Signals that carry information regarding nutritional status to the brain are essential for normal reproductive function. Studies described in this proposal will determine the role of insulin as a nutritional signal in the reproductive system and may provide new insight into disorders of insulin resistance and decreased fertility, such as polycystic ovary syndrome.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Clinical Investigator Award (CIA) (K08)
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Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
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Hyde, James F
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Johns Hopkins University
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Miller, Ryan S; Wolfe, Andrew; He, Ling et al. (2012) CREB binding protein (CBP) activation is required for luteinizing hormone beta expression and normal fertility in mice. Mol Cell Biol 32:2349-58
Brothers, Kathryn J; Wu, Sheng; DiVall, Sara A et al. (2010) Rescue of obesity-induced infertility in female mice due to a pituitary-specific knockout of the insulin receptor. Cell Metab 12:295-305