Direct Regulation of GnRH neuronal function by P13K activity

描述(申请人提供)：繁殖成功在很大程度上取决于生物体的营养状态。虽然代谢和营养对生育的影响机制尚不清楚，但代谢紊乱和不孕症之间存在着很强的联系。我们推测，许多不孕症是由于外周代谢信号调节促性腺激素释放激素(GnRH)分泌的改变所致。磷脂酰肌醇-3-激酶(PI3K)是葡萄糖、胰岛素和瘦素等外周代谢信号的关键下游靶点。我们假设PI3K是调节GnRH神经元激活的代谢和神经信号的关键整合因子。本研究的具体目的如下：1)研究PI3K是否通过代谢信号调节GnRH神经元；2)确定负能量平衡条件下GnRH神经元特异性PI3K活性是否发生改变；3)GnRH神经元特异性PI3K缺失对生殖轴的影响；4)GnRH神经元特异性PI3K信号通路调控基因的表达。该奖项的目的是提供必要的培训，以促进博士后实习生过渡到独立的教员职位。乔恩·莱文博士的指导以及同事的培训和资源将帮助阿科斯塔博士获得指导阶段所需的技能和实验结果。这项培训将包括寻找教员职位。西北大学将提供实现这一目标所需的设施和教育环境。具体地说，阿科斯塔博士在这段指导期间取得的成就将帮助她制定一个成功的独立研究计划，旨在利用遗传学和生理学体内实验模型，研究控制下丘脑促性腺激素分泌的分子机制。目前，在我们的社会中，肥胖和2型糖尿病的发病率不断上升。这些疾病加剧了女性的内分泌紊乱，如多囊卵巢综合征(PCOS)。这项提案中概述的研究与NICHD的使命高度相关，因为它寻求解决与代谢紊乱相关的不育症的原因。

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.