OVARIAN GROWTH FACTORS

在拟议的支持期间，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，以实现 理解水平足以在体内控制该系统。此后， 这些概念和可能的一些评价的化合物可用于 提高动物和女性的生育能力。计划的关键 研究进展是了解IGF-I系统与激素的界面， 和生长因子信号， 生殖周期划定了两个控制点：（1） 颗粒细胞中IGF-I生物合成的生理控制。在这一领域， 事实证明，我们的系统具有独特的信息量。具体目标1： 继续这些研究，以确定在分子方面的相互作用，FSH和 其在IGF-I启动子上的环AMP依赖性级联。示范效果 该基因的其他刺激物的表达将被追踪到其他启动子元件。 为了在体内测试这些调控原则，表达IGF-I启动子 将在转基因小鼠中测试转基因。(2)在具体目标2中， 影响IGF-I基因的细胞机制将扩展到其他细胞， 卵巢细胞的功能。这一具体目标的目的是 了解IGF与FSH的相互作用， 颗粒细胞复制，存活和分化在不同的时间， 卵泡的寿命。这些研究将制定详细的 介导这些效应的信号转导途径的图片。 具体目标3采用转基因方法来检验所得出的假设 来自特定目的1和2中的早期描述性研究和体外研究 通过体内转基因方法。控制目标和 研究将包括IGF-I的局部合成和IGF-I的作用 通过其受体介导的多点磷酸化 从这个受体发出的级联反应。这些研究中的大多数具有临床意义。 相关性，因为要检查的信号级联的抑制剂是 因为有足够数量的各种IGF 衍生物现在可用于人类作为可能的放大 排卵机制然而，最直接的一系列实验 临床相关性是那些寻求使用条件性转基因 建立多囊卵巢胰岛素抵抗模型的技术 综合征如果成功的话，这种模式可能会为批判性评估打开大门， 理解和治疗方式。

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.