CAREER: The Function of Nuclear-Cytoskeletal Tethers in Cell Mechanosensing

该学院早期职业发展（CAREER）奖的研究目标包括回答一个重要的基本问题：细胞核和细胞骨架之间的机械连接如何控制关键细胞功能，如细胞机械传感，细胞运动和细胞粘附？机械力控制着组织的体内发育，对于人工动脉和组织工程心脏瓣膜等组织替代品的体外发育至关重要。细胞感知机械刺激并将其转化为信号反应的分子机制还不清楚。该研究方法结合了工程技术对细胞施加受控的机械刺激，以及分子生物学技术干扰连接细胞核和细胞骨架的nesprin蛋白的功能。提出了以下目标：1）确定nesprin家族蛋白控制细胞感受力的机制。2)检验核-细胞骨架连接调节细胞对底物刚性的感知的假设。3)确定巢蛋白在细胞核和细胞骨架之间传递机械力的程度。这项工作将导致更好地了解组织发育，其中机械力控制发育基因表达，胚胎发生和组织图案。拟议的研究将发展细胞机械传感的分子水平的理解。因此，它将有助于工程策略的成功，这些策略使用机械力来开发具有改进性能的组织替代品。鉴于对组织替代品的需求不断增长，这项研究具有造福社会的巨大潜力。该教育计划将在奖励期间影响不同层次的学生，包括初中和高中学生，以及来自代表性不足群体的本科生。

The research objective of this Faculty Early Career Development (CAREER) award consists of answering an important, fundamental question: how does mechanical connectivity between the nucleus and the cytoskeleton control key cell functions like cell mechanosensing, cell motility and cell adhesion? Mechanical forces control the in vivo development of tissues and are crucial for the in vitro development of tissue substitutes like artificial arteries and tissue-engineered heart valves. The molecular mechanisms by which cells sense mechanical stimuli and transduce them into signaling responses are not well-understood. The research approach combines engineering techniques to apply controlled mechanical stimuli to cells, with molecular biology techniques to interfere with the function of nesprin proteins that physically link the nucleus and the cytoskeleton. The following objectives are proposed: 1) Determine the mechanism by which nesprin family proteins control cell sensing of applied forces. 2) Test the hypothesis that nuclear-cytoskeletal linkages regulate cell sensing of substrate rigidity. 3) Determine the extent to which nesprins transfer mechanical force between the nucleus and the cytoskeleton. This work will lead to improved understanding of tissue development where mechanical forces control developmental gene expression, embryogenesis and tissue patterning. The proposed research will develop molecular-level understanding of cell mechanosensing. Consequently, it will aid the success of engineering strategies which use mechanical forces for developing tissue substitutes with improved performance. Given the ever-growing need for tissue substitutes, this research has strong potential for benefitting society. The educational program will impact students at different levels over the award period including middle and high school students, and undergraduate students from under-represented groups.