Aging and Leydig Cell Function

描述（由申请人提供）：血清睾酮水平随着男性年龄的增长而下降。虽然睾丸激素下降的后果尚未完全清楚，但很明显，睾丸激素减少对骨质疏松症、认知和性欲有相关的、改变生活的影响。关于睾酮下降发生的分子机制知之甚少。我们已经建立了布朗挪威大鼠作为一个适当的模型，研究人类生殖衰老的分子机制，并已表明，年龄相关的血清睾酮减少与Leydig细胞类固醇功能的缺陷。重要的是，我们发现，无论是在体内还是体外，将老的Leydig细胞暴露于LH都不会恢复这些细胞产生高水平（“年轻”）睾酮的能力，但将细胞与cAMP类似物dbcAMP一起孵育会这样做。因此，实际上，dbcAMP将逆转Leydig细胞老化！这些研究强调了在与年龄相关的类固醇生成减少中具有核心重要性的信号转导缺陷。本申请中提出的研究旨在解决Leydig细胞发生年龄相关功能变化导致雄激素形成减少的潜在分子机制。我们的总体假设是，衰老Leydig细胞信号转导级联的变化导致衰老细胞对LH的反应能力降低，从而导致cAMP减少; cAMP减少导致胆固醇转运到线粒体和类固醇生成酶活性降低;还有活性氧介导的损伤导致LH信号转导级联的变化，最终导致睾酮产生减少，这是衰老的特征睾丸间质细胞。我们将在这个修订后的竞争性更新应用程序中研究这一假设的关键组成部分，它具有以下具体目标：1。确定LH刺激导致cAMP产生减少的分子基础。2.确定cAMP恢复老化Leydig细胞睾酮产生的“年轻”水平的机制。3.确定活性氧介导的对衰老细胞中信号转导级联的特定组分的损伤是否是导致衰老Leydig细胞睾酮产生减少的分子变化的基础。

DESCRIPTION (provided by applicant): Serum levels of testosterone decline as men age. Although the consequences of the decline are not fully understood, it is clear that there are related, life-altering effects of reduced testosterone on osteoporosis, cognition, and libido. Little is known about the molecular mechanisms by which testosterone decline occurs. We have established the Brown Norway rat as an appropriate model with which to study the molecular mechanisms underlying reproductive aging in humans, and have shown that the age-related reductions in serum testosterone are associated with deficits in Leydig cell steroidogenic function. Importantly, we found that exposure of old Leydig cells to LH, whether in vivo or in vitro, will not restore the ability of these cells to produce testosterone at high ("young") levels, but that incubating the cells with the cAMP analog dbcAMP will do so. Thus, in effect, dbcAMP will reverse Leydig cell aging! These studies highlighted defects in signal transduction of central importance in age-related reduced steroidogenesis. The studies proposed in this application are designed to address the underlying molecular mechanisms by which Leydig cells undergo age-related functional changes that lead to reduced androgen formation. It is our overarching hypothesis that changes in the signal transduction cascade of aging Leydig cells result in the decreased ability of the aged cells to respond to LH and thus in reduced cAMP; that reduced cAMP is responsible for reductions in cholesterol transport into the mitochondria and in steroidogenic enzyme activities; and that reactive oxygen-mediated damage is responsible for changes in the LH signal transduction cascade that ultimately result in the reduced testosterone production that characterizes aging Leydig cells. We will examine critical components of this hypothesis in this revised competing renewal application, which has the following specific aims: 1. Determine the molecular basis for reduced cAMP production in response to LH stimulation. 2. Determine the mechanism by which cAMP restores "young" levels of testosterone production to aged Leydig cells. 3. Determine whether reactive oxygen-mediated damage to specific components of the signal transduction cascade in old cells is the basis of the molecular changes that lead to reduced testosterone production by aged Leydig cells.