CAREER: Regulation of Hyaluronan Production and Function by Biomechanical Signals

该学院早期职业发展（CAREER）补助金将调查生物力学在控制透明质酸的生产和功能中的作用。Hybryonan是体内许多组织和器官的组成部分。 它为膝关节等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和多样的，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，与它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，以及其他尚未发现的因素。这项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品的功能和相互作用的差异。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。 鉴于透明质酸几乎在身体的所有组织中产生，这一知识有可能推动科学和人类健康。 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）的了解。 教育和外联工作将作为科学研究的补充。 这些项目将针对那些通常在科学、技术、工程和数学（STEM）项目中服务不足的人群。 具体而言，这将包括纽约州首都地区的第一代大学生、高中生运动员和初中至高中生。本科生和研究生研究人员参与这些活动将提高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提示如何改变透明质酸的周转和富含透明质酸的细胞周外套的组装。利用滑膜关节细胞作为研究系统，研究目的是（1）探讨机械刺激是否以幅度和频率依赖性方式影响透明质酸合成和降解，以及（2）表征机械负荷在促炎条件下改变透明质酸周转和细胞周被膜形成的程度。实验结果将通知计算模型，建立机械线索透明质酸的合成和营业额之间的关系和由此产生的性质的透明质酸丰富的矩阵。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点上更广泛地推进知识。 这项工作的长期影响，除了未来的应用，以改善人类健康，也将扩大参与和保留的代表性不足的群体在生物力学研究和STEM事业通过外联。这个奖项反映了NSF的法定使命，并已被认为是值得的支持，通过评估使用基金会的智力价值和更广泛的影响审查标准。

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.