Direct Regulation of GnRH neuronal function by P13K activity

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DESCRIPTION (provided by applicant): Reproductive success is largely determined by the nutritional status of the organism. Although the mechanisms mediating the influence of metabolism and nutrition on fertility remain unclear, a strong association between metabolic disorders and infertility exists. We hypothesized that many cases of infertility result from alterations in the regulation of gonadotropin releasing hormone (GnRH) secretion by peripheral metabolic signals. The enzyme phosphatidylinositol-3-kinase (PI3K) is a key downstream target of peripheral metabolic signals such as glucose, insulin, and leptin. We hypothesize that PI3K is a key integrator of metabolic and neural signals regulating activation of GnRH neurons. The specific aims of this proposal are the following: 1) to investigate if PI3K mediates the control of GnRH neurons by metabolic cues; 2) to determine if GnRH-neuron-specific PI3K activity is altered during conditions of negative energy balance; 3) to determine the effects of GnRH-neuron-specific deletion of PI3K on the reproductive axis, 4) to identify GnRH-neuron-specific expression of genes involved in the regulation of the PI3K signaling pathway. The objective of this award is to provide the necessary training to facilitate the transition by a postdoctoral trainee to an independent faculty position. The mentorship of Dr. Jon Levine and training and resources of his colleagues will help Dr. Acosta obtain the skills and experimental results necessary in the mentored phase. This training will include the search for a faculty position. Northwestern University will provide the facilities and educational environment necessary to achieve this goal. Specifically, Dr. Acosta's achievements during this mentored period will help her develop a successful independent research program aimed at studying the molecular mechanisms underlying the control of hypothalamic gonadotropin secretion, using both genetic and physiological in vivo experimental models. Currently in our society there is growing incidence of obesity and type 2 diabetes. These diseases exacerbate endocrine disorders such as Polycystic Ovarian Syndrome (PCOS) in women. The research outlined in this proposal is highly relevant to the mission of NICHD as it seeks to address the causes of infertilities associated with metabolic disorders.