PROJECT 3 - IGF-I and Neuroendocrine Regulation of Female Reproductive Function

项目 3 - IGF-I 和女性生殖功能的神经内分泌调节

基本信息

批准号：
7684931
负责人：
ANNE M ETGEN
金额：
$ 38.32万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7684931
关键词：
Adrenergic Agents Adrenergic Receptor Aging Amino Acids Animals Attenuated Bioavailable Body Weight Brain Catecholamines Chronic Development Diabetes Mellitus Disease Eating Ensure Estradiol Estrogens Estrous Cycle Exposure to FOS gene Failure Female Functional disorder Gene Expression Genes Glutamates Gonadotropin Hormone Releasing Hormone Gonadotropins Hormonal Hormones Hypothalamic structure Immunoblotting Impairment In Situ Hybridization Infusion procedures Insulin-Like Growth Factor I Insulin-Like-Growth Factor I Receptor KISS1 gene Location Lordosis Luteinizing Hormone Medial Mediating Mediator of activation protein Menopause Messenger RNA Microdialysis Neurons Neurosecretory Systems Neurotransmitters Norepinephrine Ovarian Ovarian Steroid Hormone Physiological Pituitary Gland Premature Ovarian Failure Preoptic Areas Progesterone Progesterone Receptors Proteins Quality of life Rattus Receptor Signaling Regulation Reproductive Behavior Reproductive Biology Reproductive Physiology Signal Transduction Site Steroids Syndrome Testing Woman Women&apos s Health adrenergic age related aging brain early experience gamma-Aminobutyric Acid hypothalamic pituitary gonadal axis improved in vivo insight kisspeptin mRNA Expression middle age neuromechanism neuronal cell body neurotransmission novel novel therapeutics receptor relating to nervous system reproductive reproductive function reproductive success research study senescence

项目摘要

This project tests the hypothesis that insulin-like growth factor-1 (IGF-1) and its receptor are essential comediators of critical reproductive actions of estradiol (E2) in the neuroendocrine hypothalamus (HYP). We have shown that chronic intracerebroventricular infusion of an IGF-1 receptor antagonist suppresses estrous cycles, an effect that is not attributable to impaired food intake or reduced body weight. Therefore, the proposed experiments test the hypothesis that IGF-1 receptor signaling in the HYP is essential for neuroendocrine regulation of female reproductive function by E2. We will identify the mechanisms and neural sites of IGF-1 regulation of the hypothalamic-pituitary-gonadal axis by determining whether IGF-1 acts directly on the gonadotropin releasing hormone (GnRH) neurons, their afferent inputs, and/or their responsiveness to E2. Finally, we will test the hypothesis that the delayed and attenuated luteinizing hormone (LH) surge that characterizes female rats making the transition to reproductive senescence is causally related to reduced IGF-1 receptor signaling in the aging brain. Specific Aim 1 tests the hypothesis that IGF-1 regulation of the E2-dependent LH surge is mediated at the level of the HYP rather than the pituitary. Specific Aim 2 tests the hypothesis that IGF-1 regulates E2-dependent afferent signals to GnRH neurons. We will determine the effects of brain IGF-1 receptor blockade on GnRH neuronal activation under hormonal conditions that should generate LH surges. We will also determine the effects of brain IGF-1 receptor blockade on E2 regulation of progestin receptors and kisspeptin gene expression in the HYP and on the release of excitatory (glutamate) and inhibitory (GABA) neurotransmitters in medial preoptic area (HYP site of GnRH cell bodies). Specific Aim 3 tests the hypothesis that IGF-1 regulates GnRH neuronal responsiveness to E2 afferent input. We will determine the effects of brain IGF-1 receptor blockade on glutamate, kisspeptin and a1-adrenergic activation of LH release in hormone-primed females. Specific Aim 4 tests the hypothesis that declining levels of bioavailable IGF-1 are causally related to the delayed and attenuated LH surges in middle-aged females undergoing the transition to reproductive senescence. We will determine whether elevating brain IGF-1 restores hormone-dependent LH surges in middle-aged rats, and if so, whether this manipulation also restores E2 regulation of amino acid neurotransmission and of kisspeptin gene expression. These findings may provide insight into the mechanisms underlying premature ovarian failure and reproductive neuroendocrine dysfunction that accompanies diabetes and polycystic ovarian syndrome (PCOS). This could suggest new therapeutic strategies for treating reproductive disorders associated with altered IGF-1 levels, such as PCOS. They could also identify factors whose manipulation might prolong exposure of middle-aged women to the physiological benefits of ovarian steroids

该项目测试胰岛素样生长因子 1 (IGF-1) 及其受体是重要的喜剧因素这一假设雌二醇（E2）在神经内分泌下丘脑（HYP）中的关键生殖作用。我们已经表明，IGF-1受体拮抗剂的长期脑室内输注可抑制动情周期，这种效应不能归因于食物摄入量减少或体重减轻。因此，提出的实验检验了以下假设：HYP 中的 IGF-1 受体信号传导对于 E2对女性生殖功能的神经内分泌调节。我们将确定机制和神经通过确定 IGF-1 是否发挥作用，IGF-1 调节下丘脑 - 垂体 - 性腺轴的位点直接作用于促性腺激素释放激素（GnRH）神经元、它们的传入输入和/或它们的对E2的反应。最后，我们将检验以下假设：延迟和减弱的黄体化雌性大鼠向生殖衰老过渡的特征是激素（LH）激增与衰老大脑中 IGF-1 受体信号减弱有关。具体目标 1 检验假设 IGF-1 对 E2 依赖性 LH 激增的调节是在 HYP 水平介导的，而不是在垂体。具体目标 2 测试 IGF-1 调节 E2 依赖性 GnRH 传入信号的假设神经元。我们将确定大脑 IGF-1 受体阻断对 GnRH 神经元激活的影响会导致 LH 激增的荷尔蒙状况。我们还将确定大脑 IGF-1 的影响受体阻断对 HYP 中孕激素受体和 Kisspeptin 基因表达的 E2 调节的影响内侧视前区（HYP）兴奋性（谷氨酸）和抑制性（GABA）神经递质的释放 GnRH 细胞体的位点）。具体目标 3 检验 IGF-1 调节 GnRH 神经元的假设对 E2 传入输入的反应。我们将确定大脑 IGF-1 受体阻断对谷氨酸、Kisspeptin 和 α1 肾上腺素能激活荷尔蒙引发的女性中 LH 的释放。具体目标图 4 检验了以下假设：生物可利用的 IGF-1 水平下降与延迟和正在经历生殖衰老过渡的中年女性的 LH 激增减弱。我们将确定升高大脑 IGF-1 是否可以恢复中年大鼠激素依赖性 LH 激增，以及是否那么，这种操作是否也恢复了 E2 对氨基酸神经传递和 Kisspeptin 的调节基因表达。这些发现可能有助于深入了解卵巢早熟的机制伴随糖尿病和多囊卵巢的衰竭和生殖神经内分泌功能障碍综合征（多囊卵巢综合症）。这可能为治疗生殖疾病提出新的治疗策略与 IGF-1 水平改变有关，例如 PCOS。他们还可以识别操纵的因素可能会延长中年女性接触卵巢类固醇的生理益处