CAREER: Integrin-Mediated Mechanotransduction of Articular Chondrocytes

这项教师早期职业发展(CALEAR)奖将集中于阐明与骨关节炎发展相关的分子机制。骨性关节炎是一种随着年龄或受伤而发生的关节炎。机械力是骨性关节炎发生发展的关键因素。然而，对于机械力导致生物行为可能导致骨关节炎的机制，我们的理解仍然存在很大差距。这项工作将专门关注软骨中的细胞，即软骨细胞。该项目将阐明关节软骨细胞决定软骨组织健康的分子机制。具体地说，这项工作将研究机械输入与生物输出的关系，这种关系是通过通过特定的机械感受器传递力来实现的，感受器将细胞外的纤维环境与细胞内的结构组件连接起来。这项研究最终将应用于未来的生物力学或药物干预，以预防或逆转骨关节炎。这个项目的研究还将被整合到一个教育和推广计划中，该计划基于研究生和本科生课程的开发，促进研究生和本科生的研究机会，以及通过开发教育故事书和实践夏令营活动，促进K-12和地区代表性较低的少数民族的推广。研究的具体目标是确定整合素介导的机械转导机制，通过该机制关节软骨细胞调节软骨内稳态，从而促进对骨关节炎发病机制的理解。研究目标包括：(1)建立应用于软骨细胞整合素的张力的基线分解代谢阈值；(2)确定肌动蛋白动力学在多大程度上驱动软骨细胞对动态力的偏好；(3)通过施加预应激，建立表面糖蛋白作为软骨细胞整合素张力动力学的调节器。主要的重点将是利用最初为土木工程和机械工程开发的力学概念来研究由外而内的机械转导、由内向外的机械转导和分子张力整合的机制，以更好地了解整合素介导的关节软骨细胞的机械转导。教育和推广部分将把研究成果纳入研究生和本科生的课程和研究机会，向美国原住民小学生介绍细胞机械生物学原理的故事书，以及为初中生和高中生举办的实践夏令营活动。该项目将推进细胞振动分析、分子张拉完整性和细胞机械生物学的知识基础，并在纳米科学、纳米工程和生物医学工程的交叉领域奠定他的长期职业生涯。该项目由生物力学和机械生物学计划和既定的激励竞争研究计划(EPSCoR)联合资助。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

This Faculty Early Career Development (CAREER) award will focus on elucidating the molecular mechanisms associated with the development of osteoarthritis. Osteoarthritis is the type of arthritis that occurs with age or injury. Mechanical force is a key contributing factor to the development of osteoarthritis. However, substantial gaps remain in our understanding of the mechanisms by which mechanical forces lead to biological behaviors can lead to osteoarthritis. This work will focus specifically on cells in cartilage, which are called chondrocytes. This project will elucidate molecular mechanisms by which articular chondrocytes determine cartilage tissue health. Specifically, this work will examine the relation of mechanical inputs to biological outputs mediated through the transmission of forces across specific mechanoreceptors that connect the fibrous environment outside the cell with the structural components inside the cell. This research will have eventual application to future biomechanical or pharmaceutical interventions to prevent or reverse osteoarthritis. The research from this project will also be integrated into an educational and outreach program based on graduate and undergraduate curriculum development, promotion of graduate and undergraduate research opportunities, and K-12 and regional underrepresented minority outreach through the development of educational story books and hands-on summer camp activities.The specific goal of the research is to determine the integrin-mediated mechanotransduction mechanisms by which articular chondrocytes regulate cartilage homeostasis, and thus to advance understanding of the pathogenesis of osteoarthritis. The research objectives include: (1) establishing a baseline catabolic threshold for tensile force applied to chondrocyte integrins, (2) determining the degree to which actin dynamics drives chondrocyte preference for dynamic force, and (3) establishing surface glycoproteins as modulators of chondrocyte integrin tension dynamics via application of prestress. The overarching focus will be on leveraging mechanical concepts developed initially for civil and mechanical engineering to investigate mechanisms of outside-in mechanotransduction, inside-out mechanotransduction, and molecular tensegrity to obtain a better understanding of integrin-mediated mechanotransduction in articular chondrocytes. Education and outreach components will integrate research results into graduate and undergraduate coursework and research opportunities, storybooks introducing Native American elementary students to principles of cellular mechanobiology, and hands-on summer camp activities for middle and high school students. This project will advance the knowledge base in cellular vibrational analysis, molecular tensegrity, and cellular mechanobiology and establish his long-term career at the intersection of nanoscience, nanoengineering, and biomedical engineering.This project is jointly funded by the Biomechanics and Mechanobiology Program and the Established Program to Stimulate Competitive Research (EPSCoR).This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.