CAREER: Mechanisms of Cellular Mechanotransduction at the Single Molecule Level

机械力调节从细胞分裂到细胞迁移的过程，表明物理力对大多数（如果不是全部）生命系统至关重要。这个CAREER项目的目的是通过开发新的方法来绘制和操纵活细胞中的分子力，从而彻底改变机械转导的研究。具体而言，该研究项目将重点研究整合素为基础的局灶性粘连作为力学转导的试验台模型。研究人员将采用最近开发的基于荧光的力传感器来实时和在活细胞中对整合素受体施加的机械张力进行成像。该实验平台将用于剖析化学识别和整合素激活的最早步骤，从而探索在机械张力下增强的整合素-配体键（“捕获”键）在铺展细胞的新生粘附中的存在。这些实验将确定机械力如何传递到最终影响细胞功能的粘着斑。该计划将产生一个mechanoregulatory过程的定量描述，从而提供了新的工具，广泛提高我们的理解mechanodonduction.Broader ImpactThe物理和生物科学之间的接口是一个领域丰富的问题，预计将激发许多未来几代的科学家。因此，该计划的教育目标是培养训练有素的科学家，以满足我们国家在这一领域的需求。相应地，PI将开发一个专门的生物物理学课程和现代实验室实验，将扩大多学科教育。为了接触公众并吸引下一代学生，CAREER项目将开发娱乐性，信息性和互动性的动画，说明与机械生物学有关的基本概念。通过有针对性地传播给高中教师，YouTube，CancerQuest教育网站（拥有超过140，000名Facebook粉丝）和iTunes U，PI将与从外行到大学预科生的观众分享这些动画。 通过利用已经在埃默里大学实施的GK-12和HHMI资助计划，并通过启动亚特兰大地铁公立高中的外展计划，该项目将吸引年轻人学习物理和生物科学。该计划代表了一项综合努力，将利用现有资源提高公众的科学素养，并吸引学生参加跨越细胞生物学和生物物理化学领域的多学科研究计划。该补助金由分子和细胞生物科学部的细胞动力学计划和化学部的生命科学化学计划共同资助。

Intellectual MeritMechanical forces regulate processes ranging from cell division to cell migration, indicating that physical forces are critical to most, if not all, living systems. The aim of this CAREER project is to revolutionize the study of mechanotransduction by developing new methods to map and manipulate molecular forces in living cells. Specifically, the research project will focus on studying integrin-based focal adhesions as a test-bed model for mechanotransduction. The investigators will employ a recently developed fluorescence-based force sensor to image the mechanical tension exerted across integrin receptors in real-time and in living cells. This experimental platform will be used to dissect the earliest steps of chemical recognition and integrin activation, thus probing the existence of integrin-ligand bonds that strengthen under mechanical tension ("catch" bonds) in nascent adhesions of spreading cells. These experiments will determine how mechanical forces are transmitted to focal adhesions that ultimately influence cellular functions. The proposed program will yield a quantitative description of mechanoregulatory processes, thus providing new tools to broadly improve our understanding of mechanotransduction.Broader ImpactThe interface between physical and biological sciences is a field rich with questions that are expected to excite many future generations of scientists. Therefore, the educational goal of this program is to foster the pipeline of highly trained scientists that will fulfill our nation's needs in this area. Correspondingly, the PI will develop a dedicated biophysics course and modern laboratory experiments that will expand multidisciplinary education. To reach out to the general public and entice the coming generation of students, the CAREER project will develop entertaining, informative, and interactive animations illustrating fundamental concepts pertaining to mechanobiology. Through targeted dissemination to high school teachers, YouTube, the CancerQuest educational website (with over 140,000 Facebook fans), and iTunes U the PI will share these animations with audiences ranging from the lay-person to pre-college students. By leveraging the GK-12 and HHMI grant programs already in place at Emory University, and by initiating an outreach program to Atlanta metro public high schools, the project will attract young people to the physical and biological sciences. This program represents an integrated effort that will leverage existing resources to raise the scientific literacy of the general public and attract students to the fertile multidisciplinary research programs that span the areas of cell biology and biophysical chemistry.This grant is funded jointly by the Cellular Dynamics Program in the Division of Molecular and Cellular Biosciences and the Chemistry of Life Sciences program in the Division of Chemistry.