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

这个项目测试了胰岛素样生长因子-1(IGF-1)及其受体是基本喜剧演员的假设 雌激素(E_2)在神经内分泌下丘脑(HYP)的关键生殖活动。我们 研究表明，长期脑室内注射IGF-1受体拮抗剂可以抑制动情 周期，这种影响不能归因于食物摄入受损或体重减轻。因此， 拟议的实验验证了这样的假设，即HYP中的IGF-1受体信号是 雌激素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 IGF-1对下丘脑-垂体-性腺轴的调节作用 直接在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 对雌二醇的反应性。最后，我们将检验这样一种假设，即黄体生成延迟和减弱 荷尔蒙(黄体生成素)激增是雌性大鼠向生殖衰老过渡的特征 与老化大脑中IGF-1受体信号的减少有因果关系。《特定目标1》检验了假设 IGF-1对E2依赖的促黄体生成素峰的调节是在HYP水平上介导的，而不是在 脑下垂体。特异性目标2验证IGF-1调节依赖于E2的GnRH传入信号的假设 神经元。我们将确定脑IGF-1受体阻断对GnRH神经元激活的影响。 应该产生黄体生成素激增的荷尔蒙状况。我们还将确定大脑中IGF-1的作用 受体阻断剂对HYP和On中孕激素受体和Kispeptin基因表达的调节 视前内侧区兴奋性(谷氨酸)和抑制性(GABA)神经递质的释放 GnRH细胞体的位置)。特异靶3验证IGF-1调节GnRH神经元的假说 对E2传入输入的反应性。我们将确定脑内IGF-1受体阻断对血管紧张素转换酶的影响 谷氨酸、Kispeptin和A1-肾上腺素能激活荷尔蒙刺激的雌性黄体生成素释放。特定目标 4检验了这一假设，即生物可利用的IGF-1水平下降与迟缓和 处于生殖衰老过渡期的中年女性黄体生成素激增减弱。我们会 确定升高大脑IGF-1是否能恢复中年大鼠激素依赖的促黄体生成素激增，以及 那么，这种手法是否也恢复了E2对氨基酸神经传递和Kispeptin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发病机制。 糖尿病和多囊卵巢伴发的衰竭和生殖神经内分泌功能障碍 综合征(PCOS)。这可能为治疗生殖障碍提供新的治疗策略。 与IGF-1水平改变有关，如多囊卵巢综合征。他们还可以识别其操控因素 可能会延长中年女性接触卵巢类固醇的生理益处

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