Cellular and Molecular Mechanisms of Inhibin Action on the Skeleton

描述(申请人提供)：这项建议的目的是确定抑制素的细胞和机制的作用，因为它涉及骨形成。这一建议的重点是确定抑制素对骨骼施加双峰调节的分子机制，即短期暴露抑制成骨细胞的形成，长期持续暴露促进骨形成。该方法将确定抑制素A对体内骨转换的双峰调控的细胞学基础，然后验证表达谱中识别的三个特定基因IGF-1、VEGFA和BMP5的参与，并以IGF-1为优先，以确定它们参与抑制素A调控的骨代谢。这将具体由AIM1：确定抑制素A在持续暴露于抑制素A的时间过程中对骨细胞组成和骨转换的影响来执行。目的：测定抑制素A在体内外调节胰岛素样生长因子-1(IGF-1)以改变成骨细胞生成和骨形成的程度。目的：确定抑制素A对骨代谢的影响是否通过IGF-1的变化来实现，以及IGF-1是否介导了抑制素A对骨骼的作用。所涉及的方法包括RT和实时聚合酶链式反应、免疫中和实验、静态和动态组织形态计量学、免疫组织化学和细胞培养。这一建议对骨骼领域来说是一个新颖而有益的想法。骨质疏松症是一种在男性和女性中都普遍存在的疾病。骨质流失的一个主要原因是与衰老相关的性腺功能丧失。最近发现的抑制素对骨骼的合成代谢作用使该领域离找到另一种可能的治疗方法又近了一步。然而，具体行动尚不清楚。这项提议试图确定这些行动机制。

DESCRIPTION (provided by applicant): The purpose of this proposal is to identify the cellular and mechanistic actions of Inhibin as it involves bone formation. The focus of this proposal is to determine the molecular mechanisms by which Inhibins exert a bimodal regulation on the skeleton such that short-term exposure represses osteoblastogenesis and long-term continuous exposure stimulates bone formation. The approach will be to determine the cellular basis of the bimodal regulation of Inhibin A on bone turnover in vivo, and then to validate the involvement of three specific genes identified in expression profiling, IGF-1, VEGFA and BMP5 with IGF-1 the priority, to determine their involvement in Inhibin A-regulated bone metabolism. This will be specifically performed by, AIM1: Determining the effects of Inhibin A on the cellular composition of bone and bone turnover across a time course of continuous Inhibin A exposure. AIM 2: Determining the extent to which Inhibin A regulates IGF-1 in vitro and in vivo to alter osteoblastogenesis and bone formation. AIM 3: Determining if the effects of Inhibin A on bone metabolism are mediated by changes in IGF-1, and whether IGF-1 mediates Inhibin A action on the skeleton. The methods involved will include RT and real time PCR, immunoneutralization experiments, static and dynamic histomorphometry, immunohistochemistry and cell cultures. This proposal is a novel and beneficial idea to the bone field. Osteoporosis is a disease that has become a prevalent problem in both men and women. A primary cause of bone loss is loss of gonadal function associated with aging. Recent identification of the anabolic action of Inhibins on bone brings the field one step closer to finding another possible treatment. However, the action is not known. This proposal seeks to identify those mechanisms of action.