Direct Regulation of GnRH Neuronal Function by P13K Activity

Reproductive success is largely determined by the nutritional status of the organism. Although the mechanisms mediating the influence of metabolism and nutrition on fertiliy remain unclear, a strong association between metabolic disorders and infertility has been demonstrated. I hypothesize 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 including glucose, insulin, and leptin, I hypothesized that P13K is a key integrator of metabolic and neural signals regulating activation of GnRH neurons. The neuropeptide kisspeptin (KiSS-1) is one of these neural signals that has been shown to be essential for the initiation and maintanace of the reproductive axis In mammals. Recent studies suggest that KiSS-1 neurons relay metabolic Information to GnRH neurons in response to perypheral metabolic cues such as leptin. Therefore, 1 proposed that GnRH neurons receive information from peripheral metabolic cues through the activation of PI3K signaling in kisspeptin neurons. To test this model the aims of this grant are the following: 1) to investigate the effects of a kisspeptin-cell-specific deletion of the leptin receptor, a known upstream regulator of PI 3 K signaling, on the reprodcutive axis 2) to determine if P13K activity in kisspeptin neurons is altered in response to metabolic challenges by monitoring the PI3K-Akt-Fox01 pathway 3) to determine the effects of a kisspeptin-cell-specific deletion of P13K on the reproductive axis. The mentorship and support of Dr. Jon E. Levine have allowed me to aquired the necessary tools and expertise to complete these experiments as an independent investigator at Stony Brook University, Medical Center. Currently, in our society there is a high incidence of obesity and type 2 diabetes. These diseases exacerbate endocrine disorders such as Polycistic Ovarian Syndrome (PCOS) in women. The research outlined in this proposal is highly relevant to the mission of NICHD as it attempts to delineate the pathways by which metabolic dysfunction may give rise to infertilities associated with altererd GnRH secretion.