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

该项目检验了一个假设，即胰岛素样生长因子1（IGF-1）及其受体是必不可少的喜剧演员雌二醇（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，慢性脑室脑室注入IGF-1受体拮抗剂可抑制发情循环，这种作用不是归因于食物摄入受损或体重减轻的作用。因此，拟议的实验检验了催眠中IGF-1受体信号传导的假设是必不可少的 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是否起作用，下丘脑 - 垂体 - 基达轴的IGF-1调节位点直接在促性腺激素释放激素（GNRH）神经元，其传入输入和/或它们的神经元上对E2的响应。最后，我们将测试延迟和减弱黄体化的假设雌性大鼠的激素（LH）激素激素激增向生殖衰老过渡为因果关系与衰老大脑中的IGF-1受体信号传导降低有关。特定目标1检验假设 E2依赖性LH激增的IGF-1调节是在催眠水平上介导的，而不是垂体。具体目标2检验了IGF-1调节E2依赖性传入信号的假设神经元。我们将确定脑IGF-1受体阻断对GNRH神经元激活下的影响应产生LH的激素条件。我们还将确定大脑IGF-1的影响受体阻断孕激素受体的E2调节和hyp肽基因表达在催眠和on 兴奋性（谷氨酸）和抑制性（GABA）神经递质的释放（催眠） GNRH细胞体的位置）。特定目标3检验了IGF-1调节GNRH神经元的假设对E2传入输入的响应。我们将确定大脑IGF-1受体阻滞对谷氨酸，亲吻肽和抗激素释放女性LH释放的A1-肾上腺素能激活。具体目标 4检验以下假设：可生物利用的IGF-1水平下降与延迟和中年女性的LH潮流正在过渡到生殖衰老。我们将确定抬高脑IGF-1是否会恢复中年大鼠中依赖激素的LH涌现，以及是否恢复因此，这种操作是否还恢复了氨基酸神经传递和亲吻蛋白的E2调节基因表达。这些发现可能会洞悉卵巢过早的机制伴有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（PCOS）。这可能建议治疗生殖疾病的新治疗策略与改变的IGF-1水平（例如PCOS）相关。他们还可以确定操纵的因素可能会延长中年妇女对卵巢类固醇的生理益处的暴露