MECHANISMS OF REPRODUCTIVE AGING

描述：（从申请人的描述扫描）：尽管激烈 研究表明，女性生殖衰老的机制仍然存在， 不太了解。下丘脑缺陷被认为发挥了作用，如先前 到成为无周期，中年大鼠显示出显着衰减的 发情前期LH激增，并具有显著较低的激活GnRH数量 下丘脑的神经元我们假设， 中年大鼠动情前期GnRH神经元的缺失可能是由于 谷氨酸系统是一个主要的兴奋性递质系统， GnRH分泌。我们的初步研究支持这一假设， 表明GnRH对谷氨酸激动剂的反应显着 在中年大鼠动情前期减弱。形成的物理机制 中年动情前期大鼠GnRH对谷氨酸的反应减弱 这是一个不明确的问题，也是这项资助的主要重点。目标1将使用 微透析来测量谷氨酸和天冬氨酸的释放速率， 测定青年和中年动情前期大鼠下丘脑的 GnRH神经元的兴奋性氨基驱动是否受损。目的2 将确定中年人谷氨酸反应性的降低是否 大鼠动情前期可能是由于年龄相关的离子型减少， 下丘脑的谷氨酸受体目标3将审查 谷氨酸受体的锚定/聚簇蛋白（PSD 95，Chapsyn-110， GRIP），因为这些蛋白质的缺陷将 导致谷氨酸无效突触靶向、聚集和锚定 受体，与相应的损失谷氨酸的行动。目标4将决定 是否年龄相关的缺陷存在于一氧化氮（NO）系统中， 下丘脑，因为NO是GnRH神经元活化的主要调节剂， 谷氨酸作用的关键介质。为了证明一个已识别的 缺陷和减毒LH峰，我们将使用逆转录病毒基因转移 技术来纠正缺陷，看看这是否会导致恢复 LH升高并延长周期性。总体而言，拟议的研究将提供 重要的见解，为什么谷氨酸信号是妥协的， 下丘脑的中年大鼠，并将推进我们的理解， 生殖老化

DESCRIPTION: (Scanned from the applicant's description): Despite intense investigation, the mechanisms underlying reproductive aging in females remains poorly understood. A hypothalamic defect is suggested to play a role, as prior to becoming acyclic, middle-aged rats display a significant attenuation of the proestrous LH surge and possess a significantly lower number of activated GnRH neurons in the hypothalamus. We hypothesized that the decreased activation of GnRH neurons on proestrus in the middle-aged rat could be due to a defect in the glutamate system, which is a major excitatory transmitter system regulating GnRH secretion. Our preliminary studies support this hypothesis as we demonstrated that the GnRH response to glutamate agonists is significantly attenuated in the middle-aged rat on proestrous. The mechanism responsible for the attenuated GnRH response to glutamate in the middle-aged proestrous rat remains unclear and is the primary focus of this grant. Aim 1 will use microdialysis to measure glutamate and aspartate release rates in the hypothalamus of the middle-aged and young proestrous rat in order to determine whether there is a compromised excitatory amino drive to GnRH neurons. Aim 2 will establish whether the reduced glutamate responsiveness in the middle-aged rat on proestrus could be due to an age-related reduction in ionotropic glutamate receptors in the hypothalamus. Aim 3 will examine the status of anchoring/clustering proteins for glutamate receptors (PSD95, Chapsyn-1 10, GRIP) in the middle-aged proestrous rat since a defect in these proteins would lead to ineffective synaptic targeting, clustering and anchoring of glutamate receptors, with a corresponding loss of glutamate action. Aim 4 will determine whether an age-related defect exists in the nitric oxide (NO) system in the hypothalamus, since NO is a major regulator of GnRH neuronal activation and a key mediator of glutamate effects. To prove causation between an identified defect and the attenuated LH surge, we will use retroviral gene transfer technology to correct the defect and see if this leads to reinstatement of the LH surge and extends cyclicity. As a whole, the proposed studies will provide important insights as to why glutamate signaling is compromised in the hypothalamus of the middle-aged rat, and will advance our understanding of reproductive aging.