Mechanical control of cell growth and differentiation

描述（由申请人提供）：大多数真核细胞类型，尤其是来源于软组织的原代细胞，即使在其化学环境保持恒定时，也对其底物物理性质的变化非常敏感。特别地，一些细胞可以通过称为durosensing的过程来感知其周围细胞外基质（ECM）的刚性。现在许多研究报告了对基质硬度的强烈细胞反应，但仍不清楚细胞如何测量硬度并将机械信号转化为生化信号。不同细胞响应的刚度的大小的描绘，并确定参与粘着斑形成的几种蛋白质的基本作用奠定了基础，定义细胞如何传递力，并将它们传递给在细胞/基质界面处的力施加位点的近端或远端的化学信号。该竞争性修订建议扩大题为“细胞生长和分化的机械控制”的项目R 01 GM 083272的工作范围，该项目旨在了解细胞机械传感。本次修订的目的1建立在一个项目的初步研究，以确定细胞测量基板刚度的机制的物理和分子细节。目标2旨在开发和测试新一代模型，以解释由具有生物聚合物的异常大的长度，刚度和连接性的细丝形成的网络的弹性。细胞骨架和ECM力学理论的发展，使本修订版中提出的工作和测试的母项目中产生的数据，有可能产生新的仿生材料的重要设计原则。该项目的成功结果将有助于在与化学刺激信号相同的细节水平上定义机械信号的机制，并可能导致在纤维化，肿瘤生长和伤口愈合受损等情况下基于物理的治疗干预。 公共卫生相关性：NOT-OD-09-058 NIH宣布恢复法案基金可用于竞争性修订申请附件是要求对我的5 R 01 GM 083272 -02标题为“细胞生长和分化的机械控制”进行竞争性补充的所需文件。“我要求为两名雇员提供173,250美元（110,000美元直接）的额外资金，作为保留，如果没有资金，这些现有职位将结束，加上一些用品，以执行提案中规定的额外/增强的研究目标。

DESCRIPTION (provided by applicant): Most eukaryotic cell types, especially primary cells derived from soft tissues are exquisitely sensitive to changes in the physical properties of their substrates even when their chemical environment is held constant. In particular, some cells can sense the rigidity of their surrounding extracellular matrix (ECM) through a process which has been termed durosensing. Many studies now report strong cellular responses to substrate stiffness, but it remains unclear how cells measure rigidity and convert mechanical cues into biochemical signals. Delineation of the magnitude of stiffness to which different cells respond, and identification of essential roles for several proteins involved in formation of focal adhesion sites has laid the groundwork for defining how cells transmit forces and transduce them to the chemical signals at sites proximal or distal to the site of force application at the cell/substrate interface. This competitive revision proposes to expand the scope of work in the project R01GM083272 entitled "Mechanical control of cell growth and differentiation" that is directed at understanding cellular mechanosensing. Aim 1 of this revision builds on preliminary studies for a project to identify the physical and molecular details of the mechanisms by which cells measure substrate stiffness. Aim 2 is designed to develop and test a new generation of models to account for the elasticity of networks formed by filaments with the unusually large length, stiffness, and connectivity of biopolymers. Development of a theory for cytoskeletal and ECM mechanics, enabled by the work proposed in this revision and tested by the data generated in the parent project, has the potential to produce important design principles for new biomimetic materials. Successful outcome of this project would help define the mechanisms of mechanical signaling at the same level of detail as that of signaling by chemical stimuli, and might lead to physics-based therapeutic interventions in such settings as fibrosis, tumor growth and impaired wound healing. PUBLIC HEALTH RELEVANCE: NOT-OD-09-058 NIH Announces the availability of recovery act funds for competitive revision applications Attached are the required documents requesting a competitive supplement to my 5 R01 GM083272-02 titled "Mechanical control of cell growth and differentiation." I am requesting additional funds in the amount of $173,250 ($110,000 directs) for two employees both as a retention where these current positions will end if not funded plus a few supplies to perform additional/enhanced research aims defined in the proposal.