NSF/MCB-BSF: DYNAMIC MEASUREMENTS OF NUCLEAR MECHANOTRANSDUCTION IN SKELETAL MUSCLE CELLS IN VITRO AND IN VIVO

有机体中的细胞对机械力作出反应，使细胞能够适应其物理环境。这种“机械转导”过程，即机械刺激转化为控制细胞功能的生化信号，与肌肉组织特别相关：当运动时，肌肉尺寸增加（肥大），而缺乏活动导致肌肉逐渐损失（萎缩）。肌肉细胞“感知”机械输入的潜在机制尚不清楚。这个项目检验了一个假设，即细胞核作为细胞的机械传感器，储存着细胞的基因组信息。该项目的多元化和多学科研究为生物和工程专业的学生提供了一个良好的训练环境。作为新创建的拓展模块的一部分，拉默丁实验室将接待和指导高中和康奈尔大学的大一预科学生，特别是少数族裔和第一代大学生。这项工作将涉及发展先进的高分辨率成像方法，结合亚细胞力学的遗传和机械扰动。这个项目将提供在肌肉收缩过程中作用在细胞核上的力和诱导细胞核变形的测量。结合对诱导的基因组组织和基因表达变化的分析，该研究将回答肌肉细胞中核的力诱导变形是否/如何诱导基因表达的适应性反应。从该项目中获得的见解不仅对理解肌肉如何适应机械刺激至关重要，而且还将为其他细胞（如骨骼或血管中的细胞）如何响应其动态机械环境提供线索。这项研究是由以色列和美国的一个联合项目资助的，其中美国国家科学基金会为位于纽约康奈尔大学的美国实验室提供资金，而以色列的美以两国科学基金会（BSF）为位于雷霍沃特的魏茨曼科学研究所的以色列合作实验室提供资金。

Cells in an organism respond to mechanical forces, enabling the cells to adapt to their physical environment. This "mechanotransduction" process, in which mechanical stimuli is translated into biochemical signals that control cellular functions, is particularly relevant in muscle tissue: when exercised, muscle increases in size (hypertrophy), while lack of activity results in progressive muscle loss (atrophy). The underlying mechanism by which muscle cells "sense" the mechanical input remains unclear. This project examines the hypothesis that the nucleus, which houses the cell's genomic information, serves as a cellular mechanosensor. The diverse and multidisciplinary research in this project provides an outstanding training environment for biology and engineering students alike. The Lammerding lab will host and mentor high-school and Cornell pre-freshmen students, particularly underrepresented minority and first-generation college students, as part of newly created outreach modules. The work will involve the development of advanced high resolution imaging approaches in combination with genetic and mechanical perturbation of subcellular mechanics. This project will provide measurements of the forces acting on the nucleus during muscle contraction and of the induced deformation of the cell nucleus. Coupled with an analyses of the induced changes in genome organization and gene expression, the research will answer if/how force-induced deformation of the nuclei in muscle cells can induce adaptive responses in gene expression. Insights gained from this project are not only critical for understanding how muscles adapt to mechanical stimuli, but will also provide clues into how other cells, such as those in bones or blood vessels, respond to their dynamic mechanical environments. This research was funded by a joint Israeli and United States program in which the NSF provides funding for the US laboratory, located at Cornell University in New York, while the US-Israel Binational Science Foundation (BSF)in Israel provides funds for the collaborating Israeli lab at the Weizmann Institute of Science in Rehovot.