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

NSF/MCB-BSF：体外和体内骨骼肌细胞核力传导的动态测量

• 批准号: 1715606
• 负责人: Jan Lammerding
• 金额: $ 44.18万
• 依托单位: Cornell University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1715606&HistoricalAwards=false
• 关键词: NSF; MCB; BSF; DYNAMIC; MEASUREMENTS

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.

生物体中的细胞对机械力做出反应，使细胞能够适应其物理环境。这种“机械传导”过程，其中机械刺激被转化为控制细胞功能的生化信号，在肌肉组织中特别相关：当运动时，肌肉尺寸增加（肥大），而缺乏活动导致进行性肌肉损失（萎缩）。肌肉细胞“感知”机械输入的潜在机制仍不清楚。该项目检验了细胞核作为细胞机械传感器的假设，其中包含细胞的基因组信息。该项目的多样化和多学科研究为生物学和工程学学生提供了出色的培训环境。Lammerding实验室将接待和指导高中和康奈尔大学的新生，特别是代表性不足的少数民族和第一代大学生，作为新创建的外展模块的一部分。这项工作将涉及先进的高分辨率成像方法的发展，结合遗传和机械扰动的亚细胞力学。该项目将提供肌肉收缩过程中作用于细胞核的力的测量以及细胞核的诱导变形。再加上对基因组组织和基因表达的诱导变化的分析，该研究将回答肌肉细胞核的力诱导变形是否/如何诱导基因表达的适应性反应。从这个项目中获得的见解不仅对于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，而以色列的美国-以色列两国科学基金会（BSF）则为位于Rehospital的魏茨曼科学研究所的以色列合作实验室提供资金。

项目成果

Mutant lamins cause nuclear envelope rupture and DNA damage in skeletal muscle cells

• DOI: 10.1038/s41563-019-0563-5
• 发表时间: 2020-04-01
• 期刊: NATURE MATERIALS
• 影响因子: 41.2
• 作者: Earle, Ashley J.;Kirby, Tyler J.;Lammerding, Jan
• 通讯作者: Lammerding, Jan

Local, transient tensile stress on the nuclear membrane causes membrane rupture

核膜上的局部瞬时拉伸应力导致膜破裂

• DOI: 10.1091/mbc.e18-09-0604
• 发表时间: 2019
• 期刊: Molecular Biology of the Cell
• 影响因子: 3.3
• 作者: Zhang, Qiao;Tamashunas, Andrew C.;Agrawal, Ashutosh;Torbati, Mehdi;Katiyar, Aditya;Dickinson, Richard B.;Lammerding, Jan;Lele, Tanmay P.;Weaver, Valerie Marie
• 通讯作者: Weaver, Valerie Marie

High-throughput microfluidic micropipette aspiration device to probe time-scale dependent nuclear mechanics in intact cells

• DOI: 10.1039/c9lc00444k
• 发表时间: 2019-11-07
• 期刊: LAB ON A CHIP
• 影响因子: 6.1
• 作者: Davidson, Patricia M.;Fedorchak, Gregory R.;Lammerding, Jan
• 通讯作者: Lammerding, Jan