Cellular and Molecular Mechanisms of Inhibin Action on the Skeleton

描述（由申请方提供）：本提案的目的是确定抑制素的细胞和机制作用，因为它涉及骨形成。该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，使得短期暴露抑制成骨细胞生成，长期连续暴露刺激骨形成。该方法将确定抑制素A在体内对骨转换的双峰调节的细胞基础，然后验证在表达谱中鉴定的三个特定基因IGF-1、VEGFA和BMP 5的参与，其中IGF-1优先，以确定它们参与抑制素A调节的骨代谢。这将具体通过AIM 1进行：确定抑制素A在连续抑制素A暴露时间过程中对骨细胞组成和骨转换的影响。目的2：确定抑制素A在体外和体内调节IGF-1改变成骨细胞和骨形成的程度。目标3：确定抑制素A对骨代谢的影响是否由IGF-1的变化介导，以及IGF-1是否介导抑制素A对骨骼的作用。所涉及的方法将包括RT和真实的时间PCR，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。这对骨领域来说是一个新的有益的想法。骨质疏松症是一种疾病，已成为一个普遍的问题，在男子和妇女。骨质流失的主要原因是与衰老相关的性腺功能丧失。最近发现抑制素对骨的合成代谢作用使该领域更接近于找到另一种可能的治疗方法。然而，行动尚不清楚。本提案旨在确定这些行动机制。

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.