Direct Regulation of GnRH neuronal function by P13K activity

描述（由申请人提供）：繁殖成功在很大程度上取决于生物体的营养状况。虽然代谢和营养对生育影响的机制尚不清楚，但代谢紊乱与不孕之间存在很强的关联。我们假设许多不孕病例是由于外周代谢信号对促性腺激素释放激素（GnRH）分泌调节的改变引起的。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者。本提案的具体目的如下：1)研究PI3K是否通过代谢线索介导GnRH神经元的控制；2)确定负能量平衡状态下gnrh神经元特异性PI3K活性是否改变；3)确定gnrh神经元特异性缺失PI3K对生殖轴的影响；4)确定gnrh神经元特异性表达参与PI3K信号通路调控的基因。该奖项的目的是提供必要的培训，以促进博士后实习生向独立教师职位的过渡。Jon Levine博士的指导以及他的同事的培训和资源将帮助Acosta博士获得指导阶段所需的技能和实验结果。培训内容包括寻找教师职位。西北大学将为实现这一目标提供必要的设施和教育环境。具体来说，阿科斯塔博士在此指导期间的成就将帮助她开发一个成功的独立研究项目，旨在研究控制下丘脑促性腺激素分泌的分子机制，使用遗传和生理体内实验模型。目前在我们的社会中，肥胖和2型糖尿病的发病率越来越高。这些疾病加重了内分泌失调，如女性多囊卵巢综合征（PCOS）。本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孕症原因。

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.