CAREER: Metabolomic Analysis of Chondrocyte Mechanotransduction

这个教师早期职业发展（Career）项目将研究软骨对不同类型力的机械转导反应，并研究软骨如何使用能量。膝关节或髋关节等关节对于走路等日常活动很重要。这些活动对关节软骨产生作用力。由于超过5000万美国人患有某种类型的关节疾病，因此了解软骨对外力的反应对于改善关节功能非常重要。机械转导是软骨用来感知和响应力的过程。软骨机械转导的许多方面尚不清楚。这个项目的结果将提供一个基础的信息，将提高对软骨功能的基本理解。潜在的社会效益包括帮助科学家和工程师开发治疗关节炎等问题的新方法的新知识。软骨细胞，软骨细胞，通过已知和未知的机制对机械负荷作出反应。代谢组学分析通过使用液相色谱和质谱法定量小分子的变化来描述细胞的功能状态。该项目的第一个目标是定义软骨细胞在剪切和压缩载荷下的共同和独特的代谢组学反应。第二个目标是检查从应用压缩到软骨细胞使用的生物能机械能的转换。在这些研究中，人软骨细胞将被包裹在生理硬度的水凝胶中。这些凝胶将受到相应的机械变形，然后将提取代谢物。整体和目标代谢组学分析将用于分析软骨细胞对应用变形的反应。目标代谢组学数据将被整合到能量代谢的系统模型中，分析将检查机械变形如何改变软骨细胞的能量使用。这项工作的意义在于，通过检查对负荷的整体和靶向代谢组学反应，这些研究将为设计和管理恢复软骨和关节健康的负荷方案提供必要的知识。

This Faculty Early Career Development (CAREER) Program project will investigate cartilage mechanotransduction in response to different types of forces and examine how energy is used by cartilage. Joints such as the knee or the hip are important for everyday activity like walking. These activities result in forces on the cartilage in the joint. Because more than 50 million Americans suffer from some type of joint disease, understanding how cartilage response to forces is important for improving joint function. Mechanotransduction is the process that cartilage uses to sense and respond to forces. There are many aspects of cartilage mechanotransduction that are not yet known. The results of this project will provide a foundation of information that will improve the basic understanding of how cartilage functions. The potential societal benefits include new knowledge that will help scientists and engineers develop new treatments for problems like arthritis.Chondrocytes, the cells of cartilage, respond to mechanical loads by both known and unknown mechanisms. Metabolomic profiling describes the functional state of the cell by quantifying changes in small molecules using liquid-chromatography and mass spectrometry. The first objective of this project is to define both shared and distinct metabolomic responses for chondrocytes in shear and compressive loading. The second objective is to examine the conversion of mechanical energy from applied compression into biological energy used by chondrocytes. For these studies, human chondrocytes will be encapsulated in hydrogels of physiological stiffness. These gels will be subjected to relevant mechanical deformations, and metabolites will then be extracted. Both global and targeted metabolomic profiling will be used to analyze the responses of chondrocytes to the applied deformations. The targeted metabolomic data will be integrated into a systems model of energy metabolism, and analyses will examine how mechanical deformations alter chondrocyte energy usage. The significance of this work is that by examining both global and targeted metabolomic responses to loading, these studies will provide the knowledge necessary to design and administer loading regimes for restoring cartilage and joint health.