PHYTOESTROGEN REGULATION OF BONE TURNOVER

描述(改编自申请人的摘要)：相信 植物雌激素具有选择性的雌激素受体调节活性，因此， 这些化合物被一些人归类为SERM。在这个高度 假设驱动的应用，主要研究人员假设 植物雌激素通过与雌激素受体相互作用影响破骨细胞的形成 支持成骨细胞，从而减少其破骨细胞的表达 细胞因子，如脑脊液-1(激活FMS受体)或RANK-配体(即 激活核因子-kB途径。他还假设植物雌激素，如 金雀异黄素除了对雌激素受体起作用外，还能抑制 酪氨酸激酶通过非雌激素受体机制。因此，具体而言， 目的1，申请人建议评估植物雌激素的效果， 染料木素和大豆苷元对成骨细胞产生CSF-1和 RANK-配体，(B)破骨细胞受体及其下游信号。 L，以及(C)破骨细胞发生和破骨细胞骨形成的过程 再吸收。在具体目标2中，首席调查员打算研究 雌激素作用下植物雌激素对破骨细胞发育和功能的影响 受体要么通过反义方法消除，要么通过 使用特定的拮抗剂IC182780。出于同样的目标，研究团队将 还比较了染料木素和大豆苷元这两种植物雌激素在 有无雌激素受体的竞争分析。在……里面 具体目标3，申请人提议将非雌激素定性为 受体介导的植物雌激素对破骨细胞的作用 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、有逻辑的实验， 首席研究人员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.