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: 7568818
• 负责人: MARICEDES ACOSTA
• 金额: $ 9万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7568818
• 关键词: 1-Phosphatidylinositol 3-Kinase; Achievement; Address; Affect; Afferent Neurons; Animals; Antibodies; Award; Behavioral Assay; Brain; Breeding; Cells; Cues; Desire for food; Disease; Endocrine System Diseases; Environment; Enzymes; Experimental Models; Faculty; Female; Fertility; Food; Gene Expression; Genes; Genetic; Glucose; Goals; Gonadotropin Hormone Releasing Hormone; Gonadotropins; Green Fluorescent Proteins; Hormonal; Hormones; Hypogonadism; Hypothalamic structure; Immunohistochemistry; Incidence; Infertility; Insulin; Insulin Receptor; Insulin-Like Growth Factor I; Knockout Mice; Leptin; Mediating; Mentors; Mentorship; Metabolic; Metabolic Diseases; Metabolism; Mission; Modeling; Molecular; Molecular Genetics; Mus; National Institute of Child Health and Human Development; Neurons; Neurosecretion; Non-Insulin-Dependent Diabetes Mellitus; Nutritional status; Obesity; Organism; Ovarian; Pathway interactions; Peripheral; Phase; Physiological; Population; Positioning Attribute; Proto-Oncogene Proteins c-akt; Rattus; Regulation; Reproduction; Research; Research Personnel; Resources; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Societies; Somatomedins; Syndrome; Testing; Tissues; Training; Transgenic Mice; Transgenic Organisms; Universities; Woman; blood glucose regulation; energy balance; enzyme activity; feeding; food restriction; genetic analysis; in vivo; insulin signaling; mutant; nutrition; obesity treatment; pituitary gonadal axis; prevent; programs; promoter; recombinase; relating to nervous system; reproductive; reproductive axis; reproductive success; response; restoration; skills; tripolyphosphate

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.

描述（由申请人提供）：生殖成功在很大程度上取决于生物体的营养状况。尽管介导代谢和营养对生育的影响的机制尚不清楚，但代谢性疾病与不育之间存在很强的联系。我们假设许多不孕病例是由于周围代谢信号的促性腺激素释放激素（GNRH）分泌的改变而导致的。酶磷脂酰肌醇3-激酶（PI3K）是外周代谢信号（例如葡萄糖，胰岛素和瘦素）的关键下游靶标。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积分剂。该提案的具体目的是：1）调查PI3K是否通过代谢线索介导GNRH神经元的控制； 2）确定在负能量平衡条件下GNRH-NERON特异性PI3K活性是否改变； 3）确定PI3K的GnRH-Neuron特异性缺失对生殖轴的影响，4）确定与PI3K信号通路调节有关的基因的GnRH-Neuron特异性表达。该奖项的目的是提供必要的培训，以促进博士后学员到独立教师职位的过渡。乔恩·莱文（Jon Levine）博士的指导以及同事的培训和资源将帮助阿科斯塔（Acosta）博士获得指导阶段所需的技能和实验结果。该培训将包括寻找教师职位。西北大学将提供实现这一目标所需的设施和教育环境。具体而言，在这一指导期间，Acosta博士的成就将有助于她使用遗传学和生理学体内实验模型，旨在研究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型糖尿病的发生率越来越大。这些疾病加剧了女性的内分泌疾病，例如多囊卵巢综合征（PCOS）。该提案中概述的研究与NICHD的使命高度相关，因为它试图解决与代谢疾病相关的上级实用性的原因。

项目成果

Galanin-like peptide (GALP) neurone-specific phosphoinositide 3-kinase signalling regulates GALP mRNA levels in the hypothalamus of males and luteinising hormone levels in both sexes.

• DOI: 10.1111/jne.12163
• 发表时间: 2014-07
• 期刊: Journal of neuroendocrinology
• 影响因子: 3.2
• 作者: Aziz R;Beymer M;Negrón AL;Newshan A;Yu G;Rosati B;McKinnon D;Fukuda M;Lin RZ;Mayer C;Boehm U;Acosta-Martínez M
• 通讯作者: Acosta-Martínez M