Direct Regulation of GnRH neuronal function by P13K activity

繁殖的成功在很大程度上取决于生物体的营养状态。尽管这些机制 新陈代谢和营养对受精的影响尚不清楚，在 代谢紊乱和不孕不育已经被证实。我假设许多不孕不育的病例 外周代谢调节促性腺激素释放激素(GnRH)分泌的变化 信号。磷脂酰肌醇-3-激酶(PI3K)是外周代谢的关键下游靶点 包括葡萄糖、胰岛素和瘦素在内的信号，我假设P13K是代谢和 神经信号调节GnRH神经元的激活。神经肽Kispeptin(KiSS-1)就是其中之一 神经信号已被证明是生殖轴的启动和维持所必需的 哺乳动物。最近的研究表明，KiSS-1神经元将代谢信息传递给GnRH神经元。 对瘦素等外周代谢信号的反应。因此，1提出GnRH神经元接受 通过激活Kispeptin神经元中的PI3K信号，来自外周代谢信号的信息。至 测试这个模型这项资助的目的如下：1)研究一种特定于细胞的Kispeptin的效应 瘦素受体，已知的PI 3K信号的上游调节因子，在复制轴2)上的缺失 通过监测Kispeptin神经元中的P13K活性，确定其在代谢挑战时是否发生改变 PI3K-Akt-FOX01途径3)，以确定Kisspeptin细胞特异性缺失P13K对 生殖轴。乔恩·E·莱文博士的指导和支持使我获得了必要的 作为石溪大学的独立研究员，完成这些实验的工具和专业知识， 医疗中心。目前，在我们的社会中，肥胖和2型糖尿病的发病率很高。这些疾病 加重女性的内分泌紊乱，如多发性卵巢综合征(PCOS)。这项研究概述了 这项提案与日内瓦排雷中心的使命高度相关，因为它试图勾勒出 代谢功能障碍可能导致与GnRH分泌异常相关的不育症。

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.