ABSTRACT

0955291
Mofrad

Living 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.

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