OVARIAN GROWTH FACTORS

卵巢生长因子

• 批准号: 6476693
• 负责人: JAMES M HAMMOND
• 金额: $ 35.68万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-12-01 至 2003-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6476693
• 关键词: DNA footprinting; beta galactosidase; biological models; biological signal transduction; follicle stimulating hormone; gene expression; genetic promoter element; genetic regulation; genetically modified animals; graafian follicles; granulosa cell; growth factor receptors; hormone regulation /control mechanism; hyperinsulinism; insulinlike growth factor; intermolecular interaction; laboratory mouse; model design /development; ovary; phosphorylation; polycystic ovary syndrome; polymerase chain reaction; protein kinase; reproductive development; transcription factor; transfection

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.

在拟议的支持时期，我们将延长长期的 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， 评估的概念以及可能的某些化合物可用于 改善动物和最终女性的生育能力。预计的关键 进步是了解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。已经描绘了两个控制点：（1） 颗粒细胞中IGF-1生物合成的生理控制。在这个领域， 事实证明，我们的系统具有独特的信息。在特定目标1中，我们将 继续这些研究以分子术语定义FSH和 它在IGF-I启动子上的环状AMP依赖性级联反应。证明的效果 该基因的其他刺激因子将被追踪到其他启动子元素。 为了在体内测试这些调节原理，表达IGF-1启动子 转基因将在转基因小鼠中进行测试。 （2）在特定目标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。这个特定目的的目的是 了解IGF与FSH的相互作用，从而增强了FSH 颗粒细胞的复制，生存和分化在不同时间 卵巢卵泡的寿命。这些研究将开发详细的 介导这些效果的信号转导途径的图片。 特定目标3采用转基因方法来检验得出的假设 从较早的描述性研究和特定目的1和2的体外研究中 通过体内转基因方法。控制和 调查将包括局部合成IGF-I和IGF-I作用 通过其受体和磷酸化的多个点介导 源自该受体的级联反应。这些研究大多数都有临床 相关性是因为要检查信号级联的抑制剂是 成为广泛可用的，并且因为各种IGF的足够数量 现在可以在人类中使用衍生物作为可能的放大 排卵机制。但是，最直接的一系列实验 临床相关性是那些试图使用条件转基因的相关性 建立多囊卵巢胰岛素耐药模型的技术 综合征。如果成功，此模型可以打开关键评估的大门， 理解和治疗方式。