Direct Regulation of GnRH neuronal function by P13K activity

生殖成功在很大程度上取决于生物体的营养状况。虽然机制 调节代谢和营养对受精的影响尚不清楚， 代谢紊乱和不孕症的症状已经得到证实。我推测很多不孕症的病例 由于外周代谢调节促性腺激素释放激素（GnRH）分泌的改变， 信号.磷脂酰肌醇-3-激酶（PI 3 K）是外周代谢调节的关键下游靶标。 由于P13 K是代谢和瘦素信号的关键整合子， 调节GnRH神经元激活的神经信号。神经肽kisspeptin（KiSS-1）就是其中之一。 神经信号，已被证明是至关重要的启动和维持生殖轴在 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， 对外周代谢线索如瘦素的反应。因此，1提出GnRH神经元接受 通过激活kisspeptin神经元中的PI 3 K信号传导，从外周代谢线索中获得信息。到 测试这个模型，这项资助的目的如下：1）研究kisspeptin细胞特异性 在生殖轴上缺失瘦素受体，一种已知的PI 3 K信号传导的上游调节因子2）， 通过监测Kisspeptin神经元中的P13 K活性，确定Kisspeptin神经元中的P13 K活性是否因代谢挑战而改变。 PI 3 K-Akt-Fox 01通路3），以确定P13 K的Kisspeptin细胞特异性缺失对PI 3 K-Akt-Fox 01通路的影响。 生殖轴乔恩·E博士的指导和支持。莱文允许我获得必要的 作为斯托尼布鲁克大学的独立调查员， 医学中心目前，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 加剧内分泌失调，如妇女的多囊卵巢综合征（PCOS）。该研究概述了 这一建议与NICHD的使命高度相关，因为它试图描绘出 代谢功能障碍可引起与GnRH分泌改变有关的不孕。

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.