Integrative Approaches for the Study of the Fluidic Cellular Microenvironment

项目摘要 我的研究计划的总体目标是将流体定义为细胞的组成部分， 为了更好地了解微环境中流体的运动如何影响细胞， 组织突起我的实验室采用多学科方法， 微流控装置，计算流体动力学，细胞和分子生物学，以确定机制 细胞通过它感知并响应液体流动。我们特别感兴趣的是来自运动流体的力 影响细胞粘附和效应器信号传导，并进一步我们的总体目标，我们已经确定了三个具体的 兴趣：（1）解析运动流体对细胞的作用力，（2）识别 将这些力转换为生物反应，以及（3）确定分子尺度的转导是如何进行的。 协调成组织规模的反应。虽然我的训练集中在理解流体流动和运输， 癌症和脉管系统，我的独立研究实验室寻求专注于组织和过程， 其中流体运输的影响没有很好地定义，重点是发育和形态发生。 根据这些目标，在未来五年，我的研究实验室的具体目标是：（1） 工程细胞表面受体，以更好地了解高度保守的Notch家族受体如何感知流体 流动，（2）通过开发新的，集成的， 微流控和计算方法，（3）开发一类新的微流控装置，以概括 使用人源性细胞和基质的天然微环境。这项研究的结果和整合 的使能技术将有助于我的研究计划的总体目标， 以及细胞微环境中流体力的一般原理，阐明了 细胞响应这些力，并提供了新的工具，更广泛的应用中的机械转导 社区此外，本提案中开发的技术将构成开发未来 用于机械和转化应用的疾病模型。

PROJECT SUMMARY The overall objective of my research program is to define fluid as an integral component of the cellular microenvironment and to better understand how movement of fluid in the microenvironment impacts cell and tissue processes. My laboratory employs a multidisciplinary approach merging microfabrication techniques and microfluidic devices, computational fluid dynamics, and cellular and molecular biology to define the mechanisms by which cells sense and respond to fluid flow. We are specifically interested in how forces from moving fluids impact cell adhesion and effector signaling, and to further our overall goals, we have identified three specific interests: (1) resolving the forces that moving fluids impart on cells, (2) identifying the molecular machinery that transduces these forces into biological responses, and (3) determining how molecular scale transduction is coordinated into a tissue scale response. While my training focused on understanding fluid flow and transport in cancer and the vasculature, my independent research laboratory seeks to focus on tissues and processes in which the effects of fluid transport are not as well defined, with an emphasis on development and morphogenesis. In line with these objectives, over the next five years, the specific goals of my research laboratory are to: (1) engineer cell surface receptors to better understand how the highly conserved Notch family receptors sense fluid flow, (2) map forces and cellular responses to flow through porous media by developing novel, integrated microfluidic and computational approaches, (3) develop a new class of microfluidic devices to recapitulate the native microenvironment using human-derived cells and matrix. The results of this research and the integration of the enabling technologies will contribute to the overall objectives of my research program of defining the scope and general principles of fluid forces in the cellular microenvironment, illuminating the mechanisms by which cells respond to these forces, and providing new tools for broader application among the mechanotransduction community. Furthermore, the technology developed within this proposal will form the basis for developing future disease models for mechanistic and translational applications.