PHYTOESTROGEN REGULATION OF BONE TURNOVER

描述（改编自申请人的摘要）：据信， 植物雌激素具有选择性雌激素受体调节活性，因此， 这些化合物已被一些人分类为SERMs。在这个高度 假设驱动的应用程序，主要研究者假设， 植物雌激素通过与雌激素受体相互作用影响破骨细胞的生成 支持成骨细胞，从而减少其表达破骨细胞， 细胞因子，如CSF-1（激活fms受体）或RANK-配体（ 激活NF-κ B通路。他还假设植物雌激素，如 染料木黄酮除了对雌激素受体起作用外， 酪氨酸激酶通过非雌激素受体机制。因此，在具体 目的1，申请人提出评估植物雌激素的作用， 染料木黄酮和大豆苷元对（a）成骨细胞产生CSF-1和 RANK-配体，（B）骨细胞受体和CSF-1的下游信号， RANK-L，和（c）破骨细胞生成和骨形成的过程 再吸收在具体目标2中，主要研究者打算研究 植物雌激素对破骨细胞发育和功能的影响 受体或者通过反义方法消除，或者通过 使用特异性拮抗剂IC 182780。为了达到同样的目的，研究小组将 还比较了两种植物雌激素染料木黄酮和大豆黄酮的结合， 雌激素受体存在或不存在的竞争测定。在 具体目标3，申请人建议表征非雌激素 植物雌激素受体介导的骨诱导作用，特别是对 完整细胞和分离破骨细胞的破骨细胞酸分泌 膜。因此，通过一系列系统的、逻辑上设定的实验， 主要研究者建议澄清植物雌激素在 骨细胞调节

DESCRIPTION (Adapted from the Applicant's Abstract): It is believed that phytoestrogens have selective estrogen receptor modulatory activity and, hence, the compounds have been classified by some as SERMs. In this highly hypothesis-driven application, the principal investigator postulates that phytoestrogens affect osteoclastogenesis by interacting with estrogen receptors on supporting osteoblasts, thus reducing their expression of osteoclastogenic cytokines, such as CSF-1 (that activates the fms receptor) or RANK-ligand (that activates the NF-kB pathway. He also hypothesizes that phytoestrogens, such as genistein, in addition to their action on the estrogen receptor, also inhibit tyrosine kinase through a non-estrogen receptor mechanism. Thus, in Specific Aim 1, the applicant proposes to assess the effects of phytoestrogens, genistein and daidzein, on (a) osteoblastic production of CSF-1 and RANK-ligand, (b) osteoclastic receptors and downstream signals for CSF-1 and RANK-L, and (c) the processes of osteoclastogenesis and osteoclastic bone resorption. In Specific Aim 2, the principal investigator intends to study the activity of phytoestrogens on osteoclast development and function when estrogen receptors are either eliminated through antisense approaches, or through the use of a specific antagonist, IC182780. In the same aim, the research team will also compare the binding of the two phytoestrogens, genistein and daidzein, in competition assays for the presence or absence of estrogen receptors. In Specific Aim 3, the applicant proposes to characterize the non-estrogen receptor -mediated osteoclastic effects of phytoestrogen, specifically on osteoclast acid secretion in intact cells, and in isolated osteoclast membranes. Thus, through a systematic and logically set series of experiments, the principal investigator proposes to clarify a role for phytoestrogens in bone cell regulation.