Investigating the Mechanisms of Hydrostatic Pressure-Induced Chondrogenesis

该奖项的研究目标是研究成体干细胞将静水压力转化为产生软骨基质的生物信号的基本机制。静水压力是软骨承载载荷的主要方式，并已被证明可以增强软骨细胞的基质生成。然而，令人惊讶的是，目前对静水压力如何诱导这些细胞变化知之甚少。根据该奖项进行的研究将调查钙信号、细胞骨架成分和整合素结合在将机械信号转化为生物信号中的作用。特别是，这三个要素如何在流体静压的平移中相互作用将被确定。该研究将使用药理学抑制剂、shRNA和活细胞成像来研究这种主要负载方式的机械生物学。如果成功，这些研究将为理解钙信号、细胞骨架和整合素结合如何协同诱导成体干细胞在静水压力下产生软骨基质建立一个框架。推进我们对软骨基质产生的机械调节的理解可能会导致改进的治疗干预和组织工程策略的发展，以治疗最终进展为关节炎的衰弱软骨缺陷。除了对软骨组织再生的潜在影响外，这项工作还将适用于相关组织，如半月板和椎间盘，这些组织的大部分体内负荷也由静水压力支撑。最后，该提案还包括一项与当地一所高中合作的推广计划，向学生介绍基于细胞的疗法、生物工程和实验室研究。

The research objective of this award is to investigate the fundamental mechanisms by which adult stem cells translate hydrostatic pressure into a biological signal that produces cartilage matrix. Hydrostatic pressure is the primary manner that loads are carried in cartilage and has been shown to enhance the matrix production of cartilaginous cells. However, surprisingly little is currently known about how hydrostatic pressure induces these cellular changes. Studies conducted under this award will investigate the roles of calcium signaling, cytoskeletal components, and integrin binding in translating the mechanical signal to a biological one. In particular, how these three elements interact in the translation of hydrostatic pressure will be determined. The research will use pharmacological inhibitors, shRNA and live cell imaging to investigate the mechanobiology of this dominant loading modality.If successful, these studies will establish a framework for understanding how calcium signaling, the cytoskeleton and integrin binding cooperate to induce adult stem cells to produce cartilage matrix as a response to hydrostatic pressure. Advancing our understanding of the mechanical regulation of cartilage matrix production may lead to the development of improved therapeutic interventions and tissue engineering strategies to treat the debilitating cartilage defects that eventually progress to arthritis. In addition to its potential impact on cartilage tissue regeneration, the work will be applicable to related tissues such as the meniscus and the intervertebral disc, where the majority of loading in vivo is also supported by hydrostatic pressure. Finally, the proposal includes an outreach plan in conjunction with a local high school to introduce students to cell-based therapies, bioengineering and laboratory research.