CAREER: Regulation of Hyaluronan Production and Function by Biomechanical Signals

这项教师早期职业发展（Career）资助将研究生物力学在控制透明质酸的产生和功能方面所起的作用。透明质酸是人体许多组织和器官的组成部分。它为像膝盖这样的滑膜关节提供结构支撑和润滑。透明质酸的功能及其与其他分子的相互作用是复杂多样的，尽管它的结构相对简单。透明质酸的机械和生物学作用取决于许多因素。这些可能包括它的大小，与之相互作用的分子和细胞的类型，在细胞周围形成的富含透明质酸的结构的特征，以及其他尚未被发现的因素。本研究计划将研究机械负荷如何影响关节中不同细胞类型的透明质酸的产生，以及这些透明质酸产物在功能和相互作用方面的差异。这项工作的结果将揭示机械和生物信号如何改变其生产和功能。鉴于人体几乎所有组织都会产生透明质酸，这一知识有可能促进科学和人类健康。具体来说，通过增加我们对滑膜关节（如膝盖和肘部）以及其他富含透明质酸的器官（如肠道和大脑）的知识。与科学研究相辅相成的是教育和外联工作。这些项目将针对那些通常得不到科学、技术、工程和数学（STEM）项目服务的人群。具体来说，这将包括纽约州首都地区的第一代大学生、高中学生运动员和初高中学生。本科生和研究生研究人员参与这些活动将增强这些教育计划的影响和范围。该研究的具体科学目标是发现机械线索如何改变透明质酸的周转和富含透明质酸的细胞外膜的组装。利用滑膜关节细胞作为研究系统，研究目标是：(1)探索机械刺激是否以幅度和频率依赖的方式影响透明质酸的合成和降解；(2)表征在促炎条件下机械负荷改变透明质酸转换和细胞外膜形成的程度。实验结果将为计算模型提供信息，以建立透明质酸合成和周转的机械线索之间的关系，以及由此产生的富含透明质酸的基质的特性。该项目的研究成果将对透明质酸作为滑膜关节中的机械和生物活性分子的理解产生变革性影响，并在机械生物学和透明质酸科学的交叉领域更广泛地推进知识。这项工作的长期影响，除了未来应用于改善人类健康之外，还将通过外展扩大代表性不足的群体在生物力学研究和STEM职业中的参与和保留。该奖项反映了美国国家科学基金会的法定使命，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) grant will investigate the role that biomechanics plays in controlling the production and function of hyaluronan. Hyaluronan is a component of many tissues and organs in the body. It provides structural support and lubrication for synovial joints like the knee. The functions of hyaluronan and its interactions with other molecules are complex and diverse, despite its relatively simple structure. The mechanical and biological roles of hyaluronan depend on a number of factors. These can include its size, the types of molecules and cells with which it interacts, the characteristics of the hyaluronan-rich structures that form around a cell, and other factors that remain undiscovered. This research program will study how mechanical loading affects the production of hyaluronan by different cell types in the joint, and the resulting differences in both function and interactions of these hyaluronan products. The results of this work will reveal how mechanical and biological signals can alter its production and function. Given that hyaluronan is produced in almost all tissues of the body, this knowledge has the potential to advance science and human health. Specifically, by increasing our knowledge of synovial joints (like the knee and elbow) and also other hyaluronan-rich organs such as the gut and brain. Complementary to the scientific research will be education and outreach efforts. These will target populations that are typically under-served by programs in science technology engineering and math (STEM). Specifically, this will include first-generation college students, high-school student-athletes, and middle to high school students in the Capital Region of New York State. Involvement of undergraduate and graduate student researchers in these activities will enhance the impact and reach of these educational programs.The specific scientific goal of the research is to discover how mechanical cues alter hyaluronan turnover and the assembly of the hyaluronan-rich pericellular coat. Utilizing cells of the synovial joint as a study system, the research objectives are (1) to probe whether mechanical stimuli affect hyaluronan synthesis and degradation in a magnitude- and frequency-dependent manner and (2) to characterize the extent to which mechanical loading can alter hyaluronan turnover and formation of a pericellular coat under pro-inflammatory conditions. Experimental results will inform computational models that establish the relationships among mechanical cues hyaluronan synthesis and turnover and the resulting properties of the hyaluronan-rich matrix. The research outcomes of this project will have transformative impact on the understanding of hyaluronan as both a mechanically and biologically active molecule in the synovial joint and more broadly advance knowledge at the intersection of mechanobiology and hyaluronan sciences. The long-term impacts of this work, beyond the future application to improving human health, will also broaden participation and retention of underrepresented groups in biomechanical research and STEM careers through outreach.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.