Integrative Approaches for the Study of the Fluidic Cellular Microenvironment

项目总结 我的研究计划的总体目标是将流体定义为细胞的一个组成部分 并更好地了解微环境中流体的运动如何影响细胞和 组织过程。我的实验室采用了一种多学科的方法，将微制造技术和 微流控装置、计算流体动力学以及细胞和分子生物学来定义机制 细胞通过它感知流体流动并对其做出反应。我们特别感兴趣的是流体运动产生的力 影响细胞黏附和效应器信号传递，为了推进我们的总体目标，我们确定了三个具体的 兴趣：(1)解决流体运动对细胞施加的力，(2)确定 将这些力转化为生物反应，以及(3)决定分子尺度的转导是如何 协调成组织规模的反应。虽然我的培训重点是了解流体的流动和传输 癌症和血管系统，我的独立研究实验室试图专注于 其中，流体运输的影响没有得到很好的定义，重点是发育和形态发生。 根据这些目标，我的研究实验室在未来五年的具体目标是：(1) 设计细胞表面受体以更好地了解高度保守的Notch家族受体如何感知液体 流动，(2)通过开发新的、集成的图解作用力和细胞对在多孔介质中流动的响应 微流体和计算方法，(3)发展了一类新的微流体装置，以概括 使用人类来源的细胞和基质的自然微环境。本研究的成果与集成 将有助于我的研究计划的总体目标，即定义范围 和细胞微环境中流体力的一般原理，阐明了 细胞对这些力做出反应，为更广泛地应用于机械转导提供了新的工具 社区。此外，在这项提案中开发的技术将构成未来发展的基础 机械和平移应用的疾病模型。

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.