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Structural, Molecular, and Functional Specialization in Osteocyte Mechanosensing

骨细胞机械传感的结构、分子和功能专业化

基本信息

批准号：
8713935
负责人：
MITCHELL B SCHAFFLER
金额：
$ 48.22万
依托单位：
CITY COLLEGE OF NEW YORK
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-06 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8713935
关键词：
Address Aging Anabolic Agents Biochemical Biomechanics Biomedical Engineering Bone Matrix Bone Tissue Cell physiology Cells Complex Development Dinoprostone Disease Engineering Environment Estrogens Failure Fracture Gap Junctions Goals Gonadal Steroid Hormones Grant Health In Situ In Vitro Individual Integrins Investigation Ion Channel Laboratories Lead Liquid substance Measures Mechanical Stimulation Mechanics Mediating Medicine Membrane Methods Modeling Molecular Osteocytes Outcome Pathway interactions Physiology Process Prostaglandin E Receptor Resolution Signal Transduction Site Stimulus Stress Structure System Technology Testing Theoretical model Time Tissues Translating autocrine base bone bone cell bone loss cell type college design detector experience fluid flow in vitro Model in vivo insight interdisciplinary approach mathematical model neuronal cell body new technology new therapeutic target novel prevent programs public health relevance research study response sensor shear stress skeletal theories voltage clamp

项目摘要

DESCRIPTION (provided by applicant): Osteocytes, the cells that reside within bone matrix, are the most abundant bone cells. They function as the mechanical sensors in bone, and are critical to activation and coordination of osteoclastic and osteoblastic activities by which bone adapts to mechanical usage, maintains its health and prevents fractures. The mechanisms underlying osteocyte mechanotransduction are not well understood, though changes osteocyte mechanosensitivity have been implicated in regulating the effect of both bone anabolic agents and sex hormones. We have developed engineering models which show that small whole bone strains can be amplified locally around osteocyte processes by focal attachments to the canalicular wall. Osteocyte cell bodies cannot see similar high strains as they are too compliant and lack the cellular attachments needed for local strain amplification. These mathematical models argue that the osteocyte cell process may be uniquely designed to function as a detector of small tissue strains. To test this hypothesis, we developed a broad-based multiple-PI program that combines expertise in ion channel physiology, in vivo osteocyte structure/biomechanics and bioengineering/modeling to understand how osteocytes perceive and transduce their local mechanical environment. This program will a) examine the functional polarity of osteocyte mechano- responsiveness using electrophysiological approaches on cultured osteocytes (Aim 1), b) identify the molecular components of mechanotransduction complexes in osteocytes (Aim 2), c) characterize the structure of the mechanotransduction complex in osteocytes in vivo (Aim 3) and d) build integrative mathematical models relating local hydrodynamic forces and membrane strains at osteocyte processes and cell bodies to cellular responses in vitro and in vivo (Aim 4). We have also developed a novel technology ("Stokesian" Fluid Stimulus probe) that allows us to hydrodynamically load osteocyte processes vs. cell bodies at extremely low forces (<10pN) typical of what bone cells actually experience in vivo. Expansion of this technology to interrogate mechano-responsiveness in a broad range of cell types is a developmental goal of this grant. Significance: Understanding how osteocytes "perceive" and transduce mechanical signals may provide key new insights into bone physiology leading to the identification of novel therapeutic targets against bone loss due to aging and disease.

描述（由申请人提供）：骨细胞是骨基质内的细胞，是最丰富的骨细胞。它们作为骨中的机械传感器，并且对于骨细胞和成骨细胞活动的激活和协调至关重要，通过这些活动，骨适应机械使用，保持其健康并防止骨折。骨细胞机械传导的机制还不清楚，尽管骨细胞机械敏感性的变化与骨合成代谢剂和性激素的调节作用有关。我们已经开发了工程模型，表明小的全骨应变可以局部放大周围骨细胞的过程中，局部附件的小管壁。骨细胞细胞体不能看到类似的高应变，因为它们太顺从，缺乏局部应变扩增所需的细胞附着。这些数学模型认为，骨细胞的细胞过程可能是独特的设计，作为一个检测器的小组织应变。为了验证这一假设，我们开发了一个基础广泛的多PI程序，该程序结合了离子通道生理学，体内骨细胞结构/生物力学和生物工程/建模方面的专业知识，以了解骨细胞如何感知和识别其局部机械环境。该计划将a）使用培养的骨细胞的电生理学方法检查骨细胞机械响应的功能极性（Aim 1），B）鉴定骨细胞中机械转导复合物的分子组分（Aim 2），c）表征体内骨细胞中的机械转导复合物的结构（目的3）和建立综合数学模型，将骨细胞过程和细胞体的局部流体动力和膜应变与体外和体内细胞反应联系起来（目的4）。我们还开发了一种新技术（“Stokesian”流体刺激探针），使我们能够以骨细胞在体内实际经历的典型极低力（<10 pN）对骨细胞过程与细胞体进行流体动力学加载。这项技术的扩展，以询问机械反应在广泛的细胞类型是该补助金的发展目标。重要性：了解骨细胞如何“感知”和识别机械信号可能会为骨生理学提供关键的新见解，从而确定新的治疗靶点，以对抗因衰老和疾病引起的骨丢失。