A role for annexin V in bone cell mechanotransduction

膜联蛋白 V 在骨细胞力转导中的作用

基本信息

批准号：
6783309
负责人：
Clare E Yellowley-Genetos
金额：
$ 26.08万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-09-30 至 2007-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6783309
关键词：
annexins biological signal transduction calcium channel calcium flux cell growth regulation fluid flow gene expression mechanoreceptors osteocytes protein localization protein protein interaction tissue /cell culture

项目摘要

DESCRIPTION (provided by applicant): The physical environment of the skeleton is known to play an important role in the establishment and maintenance of structurally competent bone. However, the mechanisms by which physical signals exert such biological effects are unclear. While biophysical signals elicit a variety of cellular responses in bone cells, the mechanism by which these responses are initiated is unknown. In this study we propose that annexin V (AnxV), a CA2+-dependent phospholipid binding protein, is a critical protein required for initiating mechanotransduction. AnxV has a number of attributes, which suggest that it is ideally suited for a role as a mechanoreceptor, possibly a mechanosensitive ion channel. These include the ability to function as a Ca2+ selective membrane ion channel, and the ability to interact with both extracellular matrix proteins such as collagen, and cytoskeletal elements such as actin. Hypothesis: our central hypothesis is that bone cells detect and transduce physical signals into biological responses via a mechanism requiring AnxV. Aims: Our goal is test this hypothesis by determining the role of AnxV in the response of bone cells to oscillating fluid flow, a physiologically relevant physical signal in bone. We will determine whether AnxV, in a role as a Ca2+ selective, mechanosensitive ion channel, is required for flow-induced Ca2+ influx, global increases in Ca2+i and ultimately gene expression in human osteoblast-like MG63 cells and murine osteocytic MLO-Y4 cells (Aims 1, 2 and 3). We will also determine whether expression and cellular location of AnxV are regulated by fluid flow (Aim 4). Significance: The long-term goal of these studies is to increase our understanding of how biophysical signals are selected and converted into an appropriate biological response by bone cells. Identification of critical "mechanotransducer" proteins may also provide novel targets for future therapeutic interventions in the fight against bone diseases such as osteoporosis.

描述（由申请人提供）：众所周知，骨骼的物理环境在结构性骨骼的建立和维护中发挥着重要作用。然而，物理信号发挥这种生物效应的机制尚不清楚。虽然生物物理信号在骨细胞中引发多种细胞反应，但引发这些反应的机制尚不清楚。在本研究中，我们提出膜联蛋白 V (AnxV) 是一种 CA2+ 依赖性磷脂结合蛋白，是启动机械转导所需的关键蛋白。 AnxV 具有许多属性，这表明它非常适合作为机械感受器，可能是机械敏感离子通道。这些包括作为 Ca2+ 选择性膜离子通道的功能，以及与细胞外基质蛋白（如胶原蛋白）和细胞骨架元素（如肌动蛋白）相互作用的能力。假设：我们的中心假设是骨细胞通过需要 AnxV 的机制检测物理信号并将其转换为生物反应。目的：我们的目标是通过确定 AnxV 在骨细胞对振荡流体流（骨骼中生理相关的物理信号）的响应中的作用来检验这一假设。我们将确定 AnxV 作为 Ca2+ 选择性、机械敏感离子通道，是否是流诱导 Ca2+ 内流、Ca2+i 整体增加以及最终在人成骨细胞样 MG63 细胞和鼠类骨细胞 MLO-Y4 中的基因表达所必需的细胞（目标 1、2 和 3）。我们还将确定 AnxV 的表达和细胞位置是否受流体流动调节（目标 4）。意义：这些研究的长期目标是加深我们对骨细胞如何选择生物物理信号并将其转化为适当的生物反应的理解。关键的“机械传感器”蛋白的鉴定也可能为未来对抗骨质疏松症等骨疾病的治疗干预提供新的靶点。