CAREER: A Role for Mechanics in Regulating Cellular Crosstalk within Intervertebral Joints of the Spine

该奖项全部或部分根据2021年美国救援计划法案（公法117-2）资助。该教师早期职业发展（CAREER）奖将支持脊柱中机械调节细胞通讯的新方法的研究。这项研究将集中在椎间盘关节上，这是椎骨之间的一种类似于蝴蝶结的结构，它为脊柱提供了流动性。这种缓冲也依赖于营养物质通过软骨终板的扩散。脊柱中椎间盘关节的疾病本质上是复杂的。很难将特定的病理分离到一种细胞类型或组织。然而，针对脊柱椎间盘关节的治疗通常集中在单个组织上。它们不针对邻近的组织结构，如软骨终板，尽管那里的病变与关节疾病直接相关。最近的研究提供了证据表明，软骨终板是与其周围环境的沟通。这表明软骨终板在椎间盘关节的组织沟通中起着积极的作用。该研究奖将为软骨终板的积极作用建立新的实验知识基础。具体而言，生物力学过程调节椎间盘关节组织之间的细胞通讯。这项研究的更广泛影响支持了一个长期目标，即确定更好的治疗慢性关节疾病，如背痛。这项工作还将解决在STEM领域教育种族多样性和社会经济弱势女学生的迫切需要。这项研究将直接与教育和推广计划相结合。在大学和高中水平，它将通过组织工程应用促进对肌肉骨骼组织的理解。更广泛地说，在人类健康方面，一个名为“骨骼学校”的项目将教学龄前学生运动如何影响我们的骨骼组织。这项研究的具体目标是使用新的基于细胞的人体模型来确定1）椎间盘关节内经历的特定机械微环境条件（例如，硬度、压缩或张力）对健康和患病的人软骨细胞表型和细胞外囊泡分泌的影响;和2）机械调节的软骨终板衍生的细胞外囊泡对人椎间盘细胞产生的细胞外基质的组成和机械性质的影响，以评价软骨终板-椎间盘串扰。此外，将验证参与机械转导的关键机械传感器（TRPV离子通道/整合素）的作用以及产生的人软骨终板衍生细胞外囊泡的机械和蛋白质谱。这些实验旨在针对椎间盘关节内“所有组织结构”的复杂机械生物学相互作用，重点关注软骨终板在关节生理学中的新作用。该项目将使PI能够探索机械生物学的新领域，该领域以关节串扰和细胞间通信为中心，通过机械调节的细胞外囊泡，同时在肌肉骨骼机械生物学和病理生理学方面建立长期的职业生涯。该奖项反映了NSF的法定使命，并通过使用基金会的智力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 award is funded in whole or in part under the American Rescue Plan Act of 2021 (Public Law 117-2).This Faculty Early Career Development (CAREER) award will support research on novel methods of mechanically regulated cellular communication in the spinal column. The research will focus on the intervertebral disc joint, a cushion-like structure between vertebrae, which provides mobility to the spinal column. This cushion also relies on diffusion of nutrients through the cartilage endplate. Diseases of the intervertebral disc joint in the spinal column are complex in nature. It is difficult to isolate the specific pathology to one cell type or tissue. However, treatments targeting the intervertebral disc joint of the spine have commonly focused on a single tissue. They do not target neighboring tissue structures such as the cartilage endplate, although lesions there are directly associated with joint disease. Recent studies provide evidence that the cartilage endplate is communicating with its surroundings. This suggests an active role for cartilage endplate in the tissue communication of the intervertebral disc joint. This research award will build a foundation of new experimental knowledge on the active role of the cartilage endplate. Specifically, the biomechanical processes regulating cellular communication between tissues of the disc joint. The broader impacts of this research support a longer-term goal to identify better treatment for chronic joint diseases such as back pain. The work will also address a critical need to educate ethnically diverse and socio-economically disadvantaged women students in STEM. The research will be directly integrated with the educational and outreach program. At the university and high school level, it will facilitate an understanding of musculoskeletal tissues via tissue engineering applications. More broadly in human health, a program called “Skeleton School” will teach pre-school students how exercise influences our skeletal tissues.The specific goal of this research is use novel cell-based human models to determine the effects of 1) specific mechanical microenvironmental conditions experienced within the disc joint (e.g., stiffness, compression or tension) on healthy and diseased human cartilage cell phenotype and secretion of extracellular vesicles; and 2) the effects of mechanically regulated cartilage endplate-derived extracellular vesicles on the composition and mechanical properties of extracellular matrix produced by human intervertebral disc cells in order to evaluate cartilage endplate-intervertebral disc crosstalk. In addition, the role of key mechano-sensors (TRPV ion channels/integrins) involved in mechanotransduction and the mechanical and protein profiles of human cartilage-endplate derived extracellular vesicles generated will be validated. These experiments aim to target the complex mechano-biological interplay of “all tissue structures” within the disc joint focusing on a novel role for the cartilage endplate in joint physiology. This project will allow the PI to explore novel areas of mechanobiology centered on joint crosstalk and intercellular communication via mechanically regulated extracellular vesicles while establishing a long-term career in musculoskeletal mechanobiology and pathophysiology.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.