2007 NIH Director's Pioneer Award Program (DP1)

摘要 细胞和生物体生物学的一个主要挑战是了解活细胞生理学如何 来自于单个大分子的生物物理特性。的形态和 细胞粘附、迁移和分裂所需的细胞物理行为取决于适当的 空间和时间调节的多蛋白质机器的巨大层次，称为细胞骨架。 然而，当我们获得越来越多的知识，个人的属性， 对于细胞骨架蛋白，我们对它们的自组装和物理性质知之甚少。 多蛋白质组装体，形成物理结构，将机械信息传递到细胞 长度刻度。例如，我们不明白单个分子如何产生力， 马达被细胞骨架组装体利用来调节形态发生和力的产生， 细胞水平。目前对细胞骨架的物理行为的理解 由于缺乏实验技术来探测动态结构和物理特性， 活细胞中的介观细胞骨架组装体的性质。我建议设立 研究活细胞中细胞骨架物质生物物理特性的实验工具， 将凝聚态物理学与分子细胞生物学相结合。这项工作将 确定潜在的物理涌现细胞骨架组装，并将提供预测 将我们对分子生物物理学的理解与细胞行为联系起来的分析模型。最后， 这项工作将影响疾病的治疗，这些疾病是由于身体的失调， 细胞的行为，包括癌症转移和心脏疾病。

ABSTRACT A major challenge in cell and organism biology is to understand how living cell physiology emerges from the biophysical properties of individual macromolecules. The morphological and physical behaviors of cells required for cell adhesion, migration and division depend on the proper spatial and temporal regulation of a vast hierarchy of multi-protein machines, called the cytoskeleton. However, while we are gaining increasing amounts of knowledge of properties of individual cytoskeletal proteins, we have very little knowledge about the self-assembly and physical properties of multi-protein assemblies that form physical structures to transmit mechanical information up to cellular length scales. For example, we do not understand how forces generated by individual molecular motors are exploited by cytoskeletal assemblies to regulate morphogenesis and force generation at the cellular level. Current understanding of the physical behavior of the cellular cytoskeleton has been limited both by the lack of experimental techniques to probe the dynamic structure and physical properties of mesoscopic cytoskeletal assemblies in living cells. I propose to establish the experimental tools to study the biophysical properties of cytoskeletal matter in living cells by integrating approaches from condensed matter physics with molecular cell biology. This work will identify the underlying physics of emergent cytoskeletal assemblies and will provide predictive analytical models to link our understanding of the biophysics of molecules to cell behaviors. Finally, this work will impact the treatment of diseases that are a result of misregulation of the physical behaviors of cells, including cancer metastasis and cardiac diseases.