OVARIAN GROWTH FACTORS

在拟议的支持期内，我们将延长我们长期以来的 对卵巢胰岛素样生长因子(IGF)系统的兴趣 了解程度足以在活体内控制这个系统。此后， 所评估的概念和可能的一些化合物可用于 提高动物的生育力，并最终提高妇女的生育力。投射的关键 进展是了解IGF-I系统与激素的接口 和生长因子信号在早期卵泡发育和 生殖周期。划定了两个控制点：(1) 颗粒细胞胰岛素样生长因子-I生物合成的生理调控。在这一地区， 事实证明，我们的系统具有独特的信息量。在具体目标1中，我们将 继续这些研究，从分子的角度定义FSH和FSH的相互作用 其环状AMP依赖于IGF-I启动子的级联反应。展示的效果 该基因的其他刺激物将被追踪到其他启动子元件。 为了在体内测试这些调节原理，表达IGF-I启动子 转基因将在转基因小鼠身上进行测试。(2)在具体目标2中，研究 影响IGF-I基因的细胞机制将扩展到其他 卵巢细胞功能的各个方面。这一具体目标的目标是 了解胰岛素样生长因子与促卵泡激素的相互作用 颗粒细胞在不同时期的复制、存活和分化 卵泡的寿命。这些研究将制定一项详细的 调节这些效应的信号转导通路的图片。 《特定目标3》使用转基因方法来检验所得出的假设。 来自特定目标1和2的早期描述性研究和体外研究 通过体内转基因方法。控制和控制的目标 调查将包括IGF-I的局部合成和IGF-I的作用 通过其受体和磷酸化中的多个点介导 从这个感受器发出的级联。这些研究中的大多数都有临床 相关性，因为要检查的信号级联的抑制物是 变得广泛可用，因为足够数量的各种IGF 衍生品现在可以用在人类身上，作为可能的放大 排卵机制。然而，最直接的一系列实验 临床相关的是那些寻求使用条件转基因的人 建立多囊卵巢胰岛素抵抗模型的技术 综合症。如果成功，这种模式可能会打开批判性评估的大门， 了解和治疗方式。

In the proposed period of support, we will extend our longstanding interest in the ovarian insulin-like growth factor (IGF) system to achieve a level of understanding sufficient to control this system in vivo. Thereafter, the concepts and possibly some of the compounds evaluated can be used to improve fertility in animals and ultimately women. The key to the projected advances is understanding the interface of the IGF-I system with the hormone and growth factor signals during early follicle development and the reproductive cycle. Two control points have been delineated: (1) The physiological control of IGF-I biosynthesis in granulosa cells. In this area, our systems have proven to be uniquely informative. In Specific Aim 1, we will continue these studies to define in molecular terms the interaction of FSH and its cyclic AMP-dependent cascade on the IGF-I promoter. The demonstrated effect of other stimulators of this gene will be tracked to other promoter elements. To test these regulatory principles in vivo, expression IGF-I promoter transgenes will be tested in transgenic mice. (2) In Specific Aim 2, studies of the cell machinery which impacts on the IGF-I gene will be expanded to other aspects of ovarian cell function. The goal of this specific aim is to understand the interaction of IGF with FSH which demonstrably enhances granulosa cell replication, survival and differentiation at various times in the lifespan of the ovarian follicle. These studies will develop a detailed picture of the signal transduction pathways which mediate these effects. Specific Aim 3 employs transgenic approaches to test the hypotheses derived from earlier descriptive studies and in vitro studies in Specific Aims 1 and 2 through transgenic approaches in vivo. The targets for control and investigation will include the local synthesis of IGF-I and IGF-I action mediated through its receptor and multiple points in the phosphorylation cascade which emanate from this receptor. Most of these studies have clinical relevance because inhibitors for the signal cascades to be examined are becoming widely available and because sufficient quantities of various IGF derivatives are now available to use in humans as a possible amplifying mechanism for ovulation. However, the series of experiments of most direct clinical relevance are those which seek to use conditional transgenic technology to build an insulin-resistant model of the polycystic ovarian syndrome. If successful, this model could open the door to critical evaluation, understanding, and treatment modalities.