CAREER: Integrin-Mediated Mechanotransduction of Articular Chondrocytes

该学院早期职业发展（CAREER）奖将重点阐明与骨关节炎发展相关的分子机制。 骨关节炎是关节炎的类型，发生与年龄或损伤。机械力是骨关节炎发展的关键因素。 然而，在我们对机械力导致生物学行为导致骨关节炎的机制的理解方面仍然存在很大的差距。 这项工作将特别关注软骨中的细胞，称为软骨细胞。 这个项目将阐明关节软骨细胞决定软骨组织健康的分子机制。 具体来说，这项工作将检查机械输入的生物输出的关系，通过特定的机械感受器，连接细胞外的纤维环境与细胞内的结构组件的力的传输介导。这项研究将最终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。从这个项目的研究也将被整合到一个教育和推广计划的基础上研究生和本科课程的发展，促进研究生和本科生的研究机会，和K-12和区域代表性不足的少数民族外展，通过发展教育故事书和动手夏令营活动。研究的具体目标是确定整合素，介导的机械传导机制，关节软骨细胞通过该机制调节软骨稳态，从而促进对骨关节炎发病机制的了解。研究目标包括：（1）建立施加于软骨细胞整联蛋白的张力的基线分解代谢阈值，（2）确定肌动蛋白动力学驱动软骨细胞对动力学的偏好的程度，和（3）通过施加预应力建立表面糖蛋白作为软骨细胞整联蛋白张力动力学的调节剂。总体重点将是利用最初为土木和机械工程开发的机械概念，研究由外向内的机械转导，由内而外的机械转导和分子张力整体性的机制，以更好地了解关节软骨细胞中整合素介导的机械转导。教育和推广部分将研究成果整合到研究生和本科课程和研究机会，故事书介绍美国原住民小学生的细胞机械生物学的原则，并动手为初中和高中学生夏令营活动。该项目将推进细胞振动分析、分子张拉整体性和细胞机械生物学的知识基础，并在纳米科学、纳米工程、该项目由生物力学和机械生物学计划和刺激竞争研究的既定计划（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知识价值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.