CAREER: Cellular Mechanotransduction: An Integrated Research and Education Program

0955291MofradLiving细胞能够感知机械刺激并对其做出积极反应。这个过程被称为细胞机械转导，是细胞的一项基本功能，控制着细胞的生长、增殖、蛋白质合成和基因表达。有大量的数据记录了细胞与细胞外环境的相互作用，但关于力如何影响生物信号的了解较少。更广泛地说，机械和生化途径如何相互作用的问题在很大程度上仍然没有答案。焦点粘连是细胞与环境相互作用的关键组成部分。焦点粘连形成的关键分子事件是分子机械感受器如talin和α-actinin的激活，关键连接蛋白如vinculin的激活，以及随后的焦点粘连形成分子的募集。本研究探讨了粘着斑力学转导中涉及的特定分子事件和生物物理机制。此外，这个项目旨在通过开发一个基于网络的全球工具来促进细胞机械转导领域的教育合作和知识共享的文化，该工具具有以下特点：(1)吸引普通受众和收集兴趣的介绍性互动媒体，(2)关于机械转导和知识共享的深入教育资源，(3)全球研究人员之间合作和分享思想的社交网络中心。将使用结合计算技术和最先进的实验验证来研究焦点粘连形成的关键分子机制。目前，仅靠实验本身就面临着时间和空间分辨率不足的挑战，阻碍了它们用于研究分子激活和焦点粘连形成的结构机制。计算建模和仿真的时间和空间分辨率可用于设计实验以进行验证，从而得出有影响力的结论。两种互补的计算技术，结合分子生物物理实验，被用来处理焦点粘连形成事件。分子动力学技术研究力诱导的talin和α-actinin的激活，以及vinculin在肌动蛋白细丝招募到焦点粘连中的激活，而基于试剂的生物化学模型研究各种其他分子招募到焦点粘连。本研究将探讨斑块粘连的复杂蛋白质机制之间的分子相互作用，以期揭示参与斑块粘连形成的精细结构和生物物理机制。结合使用最先进的计算技术，从分子动力学到基于代理的建模，来研究分子和细胞的机械转导现象是创新和开创性的。此外，该项目将为细胞机械转导和机械生物学方面的知识共享和研究人员之间的合作提供新的资源。这个项目的重要意义不仅在于它的近期目标是关于局部粘连的分子生物力学，而且是在更广泛的细胞力学转导研究和教育背景下。该项目旨在为理解细胞如何感知和主动响应机械刺激提供一个基本的基础。这一过程被认为在许多疾病的发生和发展中发挥作用，从心血管疾病到癌症。因此，了解机械转导的基础可以对我们预防和处理这些疾病的方法产生深远的影响。它还可以导致新的基于细胞的纳米生物技术，有一天可能能够更好地理解细胞机械转导的分子细节，走向创新应用。此外，这些研究工作还将辅之以教育和研究合作资源的编制。目前正在开发一个知识库--机械转换网站，作为一个中心，利用互动媒体和社交网络资源等有效的网络工具，将对生物学有普遍兴趣的人和生物力学专家联系起来，并将他们聚集在一起。通过这种方式，这些工具将捕捉到对机械转导的新兴趣，分享知识和专业知识，并将伟大的思想联系在一起。

0955291MofradLiving cells sense and actively respond to mechanical stimuli. This process, termed cellular mechanotransduction, is an essential function of the cell, controlling its growth, proliferation, protein synthesis, and gene expression. Extensive data exist documenting the cell's interaction with the extracellular environment, but less is known about how force affects biological signaling. More generally, the question of how the mechanical and biochemical pathways interact remains largely unanswered. Focal adhesions are a critical component of the cell's interaction with its environment. The key molecular events underlying the formation of focal adhesions are the activation of molecular mechanosensors such as talin and alpha-actinin, the activation of key linker proteins such as vinculin, and the subsequent recruitment of focal adhesion forming molecules. This study investigates the specific molecular events and biophysical mechanisms involved in focal adhesion mechanotransduction. In addition, this project aims to advance a culture of educational collaboration and sharing of knowledge in the field of cellular mechanotransduction via developing a Web-based global tool with the following features: (1) introductory interactive media to captivate a general audience and gather interest, (2) in-depth resources for education about mechanotransduction and sharing of knowledge, (3) social-networking center for collaboration and sharing of ideas between researchers across the globe.A combination of computational techniques accompanied with state-of-the-art experimental validations will be used to study the critical molecular mechanisms underlying focal adhesion formation. Experiments alone are currently challenged by a lack of both temporal and spatial resolution preventing their use for investigating the structural mechanisms underlying molecular activation and focal adhesion formation. The temporal and spatial resolution of computational modeling and simulation can be used to design experiments for validation resulting in impactful conclusions. Two complementary computational techniques, in conjunction with molecular biophysical experiments, are used to address the focal adhesion formation events. Molecular dynamics techniques investigate the force-induced activation of talin and á-actinin, and the activation of vinculin in recruitment of actin filaments to focal adhesions, while agent-based biochemical models investigate the recruitment of various other molecules to focal adhesions.Intellectual Merit. This study will investigate the molecular interactions among the complex protein machinery of focal adhesions with the hope to shed light on the exquisite structural and biophysical mechanisms involved in focal adhesion formation. The combined use of the state-of-the-art computational techniques, ranging from molecular dynamics to agent-based modeling, to investigate molecular and cellular mechanotransduction phenomena is innovative and groundbreaking. In addition, this project will produce novel resources for the sharing of knowledge and collaboration of researchers in cellular mechanotransduction and mechanobiology.Broader and Transformative Impacts. This project is important both in terms of its immediate goals with respect to molecular biomechanics of the focal adhesions, but also in the broader context of cellular mechanotransduction research and education. This project aims to propose a fundamental basis for understanding how cells sense and actively respond to mechanical stimuli. This process has been hypothesized to play a role in the initiation and progression of many diseases, ranging from cardiovascular diseases to cancer. Understanding the basis of mechanotransduction, therefore, can have a profound impact on our approaches to preventing and tackling of these diseases. It can also lead to novel cell-based nanobiotechnologies that may one day be able to harvest better understanding of the molecular details of cellular mechanotransduction toward innovative applications. In addition, these research efforts will be complemented with the production of a resource for education and research collaboration. The development of a knowledgebase is under way, Mechanotransduction.org, as a center for using effective Web-based tools such as interactive media and social networking resources to connect and bring together both people with general interest in biology and experts in biomechanics. In this way, these tools will capture new interest in mechanotransduction, share knowledge and expertise, and link great minds together.