Osteocyte Function and Effects of Mechanical Strain

描述（由申请人提供）： 虽然骨细胞占所有骨细胞的90%以上，但与其他骨细胞（成骨细胞和破骨细胞）相比，对其功能知之甚少。骨细胞是理想地位于骨中以感知机械应变并将该应变转化为骨形成和骨吸收的信号的细胞。然而，骨细胞在调节应变对骨建模和重塑的影响中的作用尚不清楚。该项目资助的目的是开发一种团队方法来确定骨细胞的功能和对机械应变的反应。待检验的假设是骨细胞感知并响应机械应变，进而发送导致骨丢失、重塑、建模或病理修复的信号。骨细胞将机械应变转化为信号的机制包括细胞内和细胞外信号传导以及骨细胞功能所必需和特异性基因的表达。该项目的具体目标是：1）确定骨细胞感受到的导致骨量变化的机械应变水平，2）。确定E11在骨细胞树突状突起的形成和功能中的作用，3）确定骨细胞中半通道的功能和调节，4）确定Dmp 1在骨细胞中的功能，和5）。将菌株大小、基因表达与生物学反应相关联。实现这些特定目标的新方法包括使用骨细胞样细胞系、表达荧光报告基因的原代骨细胞、使用生物工程技术测量单个骨细胞感受到的应变、转基因技术、骨细胞腔隙-小管系统成像的新方法，荧光图像分析以检查单细胞中的基因表达，以及体内骨细胞中的靶向基因缺失以检查由机械应变调节的基因。该计划项目由在分子生物学，生物化学，细胞生物学和生物工程领域具有特定人才，培训和专业知识的研究人员组成，他们以多学科的方式共同工作，以整合，改进和扩展方法来检查骨细胞功能和应变反应。从这些具体目标的实现中获得的知识将应用于预防和治疗由于固定、空间飞行、微损伤和骨质疏松症等疾病引起的骨丢失。

DESCRIPTION (provided by applicant): Although osteocytes make up over 90% of all bone cells, little is known about their function compared to other bone cells, the osteoblast and the osteoclast. The osteocyte is the cell ideally situated in bone to sense mechanical strain and translate that strain into signals for bone formation and bone resorption. However, the role of osteocytes in modulating strain effects on bone modeling and remodeling is unclear. This Program Project Grant was initiated to develop a team approach to determine the function of osteocytes and response to mechanical strain. The hypothesis to be tested is that osteocytes sense and respond to mechanical strain and in turn send signals that result in either bone loss, remodeling, modeling, or pathologic repair. The mechanisms whereby osteocytes translate mechanical strain into signals include intracellular and extracellular signaling and the expression of genes necessary and specific for osteocyte function. The specific aims of the program project are: 1) To determine the levels of mechanical strain sensed by the osteocyte that result in change of bone mass, 2). To determine the role of E11 in the formation and function of osteocytic dendritic processes, 3) To determine the function and regulation of hemichannels in osteocytes, 4) To determine the function of Dmp1 in osteocytes, and 5). To correlate magntitude of strain with gene expression with biological response. Novel approaches to accomplish these specific aims include the use of an osteocyte-like cell line, primary osteocytes expressing a fluorescent reporter, the use of bioengineering techniques to measure strain sensed by individual osteocytes, transgenic technology, novel means of imaging the osteocyte lacuno-canalicular system, fluorescent image analysis to examine gene expression in single cells and targeted deletion of genes in osteocytes in vivo to examine genes regulated by mechanical strain. This program project is composed of investigators with specific talents, training and expertise in the areas of molecular biology, biochemistry, cell biology and bioengineering who together work in a multidisciplinary manner to integrate, improve, and expand approaches to examine osteocyte function and response to strain. Knowledge gained from the accomplishment of these specific aims will be applied to the prevention and treatment of bone loss due to immobilization, space flight, microdamage, and disease states such as osteoporosis.