Mechanical control of cell growth and differentiation

描述（由申请人提供）：大多数真核细胞类型，特别是来自软组织的原代细胞，即使在化学环境保持不变的情况下，对其底物物理性质的变化也非常敏感。特别是，一些细胞可以通过一种被称为硬膜感应的过程感知周围细胞外基质（ECM）的硬度。许多研究报告了细胞对底物硬度的强烈反应，但细胞如何测量硬度并将机械信号转化为生化信号仍不清楚。描述不同细胞响应的刚度大小，以及确定参与黏附位点形成的几种蛋白质的基本作用，为定义细胞如何传递力并将其转化为细胞/底物界面上施力位置近端或远端的化学信号奠定了基础。该竞争性修订建议扩大R01GM083272项目“细胞生长和分化的机械控制”的工作范围，该项目旨在理解细胞机械传感。本修订的目的1建立在一个项目的初步研究基础上，该项目旨在确定细胞测量底物刚度的机制的物理和分子细节。Aim 2旨在开发和测试新一代模型，以解释由具有异常大的长度、刚度和生物聚合物连通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，由本修订中提出的工作实现，并由母项目中产生的数据进行测试，有可能为新的仿生材料产生重要的设计原则。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，并可能导致基于物理的治疗干预，如纤维化，肿瘤生长和伤口愈合受损。

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.