CAREER: Multiscale Osmotic Mechanotransduction within the Intervertebral Disc

这一学院早期职业发展(职业生涯)奖的重点是了解应用于脊柱的机械负荷如何在健康和疾病中调节细胞功能。脊柱内的间盘关节在几十年的生命中经历了数百万次的加载周期。嵌入在组织中的细胞感知并响应这些机械信号，这些信号在调节组织的动态平衡和发育方面发挥着至关重要的作用。该奖项的重点是回答有关细胞在组织内经历的机械信号的范围以及这些信号是如何被感知的基本问题。这项研究将有助于理解组织变形时溶质浓度的变化如何调节细胞在健康和疾病中的行为。这项工作的长期目标是更好地了解脊柱内的疾病过程，并为下腰痛的潜在治疗提供信息。这项研究还将通过让传统上在工程学中代表性较低的学生参与生物学和工程学交界处的跨学科骨科研究来增强多样性。扩大代表不足学生参与的具体举措包括与少数族裔服务机构建立伙伴关系，将本科生带入研究实验室，以及参与服务不足社区的中学外联活动，以提高对STEM的认识。这个项目的具体目标是评估渗透环境动力学(速率和大小)的变化以及细胞对渗透循环的敏感性的变化有助于椎间盘内疾病的进展的假说。第一个目标是利用微渗压计和分析化学技术来确定宏观(即组织水平)和微观(即细胞周围基质)尺度上的渗透循环的动力学，并确定动力学如何随着疾病的进展而变化。第二个目标是使用微流控设备、活细胞钙成像和离子通道活性的药物修饰剂来确定渗透动力学如何影响离子通道信号。该系统还将用于研究在疾病状态下增加的辅助受体的激活是否可以敏化细胞钙信号对渗透循环的反应。该项目将允许PI推进整形外科、生物力学和机械生物学方面的知识基础，并建立他在肌肉骨骼机械生物学方面的长期职业生涯。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势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 focuses on understanding how mechanical loads applied to the spine regulate cellular function in health and disease. The intervertebral disc joint within the spine undergoes millions of loading cycles during decades of life. The cells embedded within the tissue sense and respond to these mechanical signals, which play a vital role in regulating tissue homeostasis and development. This award focuses on answering fundamental questions regarding the range of mechanical signals the cells experience within the tissue and how those signals are sensed. This study will help understand how changes in solute concentration as the tissue is deformed regulates how cells behave in health and disease. The long-term goal of this work is to better understand the disease process within the spine and inform potential treatments for low back pain. This research will also enhance diversity by engaging students traditionally underrepresented within engineering in inter-disciplinary orthopaedic research at the interface of biology and engineering. Specific initiatives to broaden participation by underrepresented students include establishing partnerships with minority serving institutions, bringing undergraduates into the research lab, and participating in middle school outreach in underserved communities to promote STEM awareness. The specific goal of this project is to evaluate the hypothesis that changes in the dynamics (rate and magnitude) of the osmotic environment and change in the cells sensitivity to osmotic cycles contribute to the progression of disease within the intervertebral disc. The first objective is to utilize micro-osmometer and analytical chemistry techniques to determine the dynamics of osmotic cycles at both macro (i.e., tissue level) and micro- (i.e., within the pericellular matrix) scales and determine how the dynamics change with advancing disease. The second objective is to use microfluidic devices, live-cell calcium imaging and pharmacologic modifiers of ion channel activity to determine how osmotic dynamics influence ion channel signaling. This system will also be used to investigate whether activation of co-receptors, increased in the diseased state, can sensitize cellular calcium signaling in response to osmotic cycles. This project will allow the PI to advance the knowledge base in orthopedics, biomechanics, and mechanobiology and establish his long-term career in musculoskeletal mechanobiology.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.