CAREER: Mechanical Forces on the Nuclear Linker of Nucleoskeleton to Cytoskeleton (LINC) Complex

职业：核骨架与细胞骨架 (LINC) 复合物的核连接器上的机械力

• 批准号: 2246970
• 负责人: Daniel Conway
• 金额: $ 50万
• 依托单位: Ohio State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-10-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2246970&HistoricalAwards=false
• 关键词: CAREER; Mechanical; Forces; Nuclear; Linker

Animal cells respond to mechanical forces both in health and during mechanically caused diseases. The forces change cell signaling through a process known as mechanotransduction. Mechanical forces are known to influence fundamental cellular and tissue level functions, but the cellular sites for mechanotransduction remain poorly understood. The nucleus is the largest and perhaps most critical structure of a mammalian cell since most of the DNA is stored there. Proteins located on the outside of the nucleus experience mechanical force, and the nucleus can be seen deforming when a cell is loaded. Deformation of the nucleus by forces suggests that the nucleus could be a site for mechanotransduction. This Faculty Early Career Development (CAREER) Program research project will determine how and when the nucleus experiences mechanical force using a new kind of force transducer, and then determine how these forces regulate cellular functions. These studies have the potential to identify a new fundamental mechanism of mechanotransduction that would be present in all animals cells. Research opportunities for undergraduate and graduate students to engage in interdisciplinary research projects are planned, as well as K-12 outreach activities, and using research results to improved graduate engineering education.The nucleus is directly connected to the cytoplasmic cytoskeleton by a group of proteins that form the LINC (linker of nucleoskeleton to cytoskeleton) complex. Mutations in LINC complex proteins are associated with impaired development, human genetic diseases, and cancer; thus the linkage of the cytoskeleton to the nucleus appears to be essential to cell function and homeostasis. Proteins in the LINC complex experience mechanical force, suggesting that the LINC complex could be an important structure for mechanotransduction. The goal of this CAREER project is to develop novel force biosensors for LINC complex proteins nesprin and SUN, and then use these sensors to study the mechanical and force-dependent biochemical processes associated with the LINC complex. Identification of the relationship between nuclear force and the forces on the outside of the cell will provide a better understanding of how forces are transmitted within a cell, helping to validate or advance theories of cellular biomechanics. Additionally, the force biosensors used in this project are expressed with plasmid DNA and imaged using fluorescent microscopy, allowing for other laboratories to adopt this force measurement technique

动物细胞对健康和机械引起的疾病的机械力反应。力通过称为机械转导的过程改变细胞信号传导。已知机械力会影响基本的细胞和组织水平功能，但是机械转导的细胞位点仍然了解不足。核是哺乳动物细胞的最大，也许是最关键的结构，因为大多数DNA都存储在那里。位于细胞核外部经历机械力的蛋白质，并且在加载细胞时可以看到细胞核变形。力通过力对细胞核的变形表明核可能是机械转导的部位。这项教师早期职业发展（职业）计划研究项目将决定使用一种新型的力传感器，然后确定这些力如何调节细胞功能。这些研究有可能确定所有动物细胞中都存在的机械转导的新基本机制。计划了本科生和研究生从事跨学科研究项目的研究机会，以及K-12外展活动，并使用研究结果改善了研究生工程教育。核直接连接到形成细胞骨骼与Cytoskelecton的linkers linker cyterskempter的蛋白质的细胞质细胞骨架。 LINC复合蛋白中的突变与发育受损，人遗传疾病和癌症有关。因此，细胞骨架与细胞核的联系似乎对于细胞功能和稳态至关重要。 LINC复合体体验机械力中的蛋白质，表明LINC复合物可能是机械转导的重要结构。该职业项目的目的是为林型蛋白质和太阳开发新型的力生物传感器，然后使用这些传感器研究与林克复合物相关的机械和力依赖性生化过程。识别核力量与细胞外部力之间的关系将更好地理解细胞内部的力如何传播，从而有助于验证或推进细胞生物力学的理论。此外，该项目中使用的力生物传感器用质粒DNA表​​示，并使用荧光显微镜进行成像，从而使其他实验室能够采用这种力量测量技术

项目成果

Nuclear lamina strain states revealed by intermolecular force biosensor.

• DOI: 10.1038/s41467-023-39563-6
• 发表时间: 2023-06-30
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Danielsson, Brooke E. E.;Abraham, Bobin George;Mantyla, Elina;Cabe, Jolene I. I.;Mayer, Carl R. R.;Rekonen, Anna;Ek, Frans;Conway, Daniel E. E.;Ihalainen, Teemu O. O.
• 通讯作者: Ihalainen, Teemu O. O.

Rho activation drives luminal collapse and eversion in epithelial acini

Rho 激活驱动上皮腺泡管腔塌陷和外翻

• DOI: 10.1016/j.bpj.2023.01.005
• 发表时间: 2023
• 期刊: Biophysical Journal
• 影响因子: 3.4
• 作者: Narayanan, Vani;Purkayastha, Purboja;Yu, Bo;Pendyala, Kavya;Chukkapalli, Sasanka;Cabe, Jolene I.;Dickinson, Richard B.;Conway, Daniel E.;Lele, Tanmay P.
• 通讯作者: Lele, Tanmay P.