Direct Regulation of GnRH neuronal function by P13K activity

P13K 活性直接调节 GnRH 神经元功能

• 批准号: 8245146
• 负责人: MARICEDES ACOSTA
• 金额: $ 24.28万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-15 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8245146
• 关键词: 1-Phosphatidylinositol 3-Kinase; Academic Medical Centers; Biological Assay; Body mass index; Breeding; Catalytic Domain; Cells; Critical Pathways; Cues; Disease; Endocrine System Diseases; Enzymes; Functional disorder; Genes; Glucose; Gonadotropin Hormone Releasing Hormone; Gonadotropins; Grant; Hormonal; Hypothalamic structure; In Vitro; Incidence; Infertility; Instruction; Insulin; KISS1 gene; Knowledge; Leptin; Mammals; Mediating; Mentorship; Metabolic; Metabolic Diseases; Metabolism; Mission; Modeling; Monitor; Mus; National Institute of Child Health and Human Development; Neurons; Neuropeptides; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Export; Nutritional status; Obesity; Organism; Ovarian; Pathway interactions; Peripheral; Pituitary Gland; Receptor Gene; Receptor Signaling; Regulation; Reproduction; Research; Research Personnel; Signal Transduction; Societies; Syndrome; Testing; Thinness; Transgenic Mice; Transgenic Organisms; Woman; improved; in vivo; kisspeptin; leptin receptor; nutrition; recombinase; relating to nervous system; reproductive; reproductive axis; reproductive success; research study; response; tool

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.

生殖成功很大程度上取决于有机体的营养状况。虽然机制 调节代谢和营养对生育力的影响仍不清楚，两者之间存在很强的关联 代谢紊乱和不孕症已被证实。我推测许多不孕不育的病例都是由于 外周代谢对促性腺激素释放激素 (GnRH) 分泌调节的改变 信号。磷脂酰肌醇-3-激酶 (PI3K) 是外周代谢的关键下游靶标 信号包括葡萄糖、胰岛素和瘦素，我假设 P13K 是代谢和瘦素的关键整合者。 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 已被证明对于生殖轴的启动和维持至关重要的神经信号 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 神经元接收 通过激活 Kisspeptin 神经元中的 PI3K 信号来获取外周代谢线索的信息。到 测试该模型 该资助的目的如下： 1) 研究 Kisspeptin 细胞特异性的效果 删除生殖轴上的瘦素受体（一种已知的 PI 3 K 信号上游调节因子）2) 通过监测 Kisspeptin 神经元中的 P13K 活性是否会因代谢挑战而改变 PI3K-Akt-Fox01 通路 3) 确定 Kisspeptin 细胞特异性删除 P13K 对 生殖轴。 Jon E. Levine 博士的指导和支持使我获得了必要的知识 作为石溪大学的独立研究者来完成这些实验的工具和专业知识， 医疗中心。目前，我国社会肥胖和2型糖尿病的发病率很高。这些疾病 加剧女性内分泌失调，如多囊卵巢综合症（PCOS）。研究概述 该提案中的内容与 NICHD 的使命高度相关，因为它试图描绘出 代谢功能障碍可能会导致与 GnRH 分泌改变相关的不孕症。