The systems biochemistry of polarized cytoskeletal morphogenesis

活细胞以非随机、极化的方式组织其内部，以执行专门的生物功能。细胞极性产生于质膜、相关蛋白质和细胞质分子之间复杂的相互作用。在真核细胞中，对称性在大多数情况下最初在膜结合分子如磷脂酰肌醇脂质和Rho型GTP酶的水平上被破坏。这些保守的信号枢纽协同控制细胞形态发生和运动通过肌动蛋白细胞骨架。虽然这些密切相关的系统的许多组件已被定义，但对细胞极性和形状变化的生化机制知之甚少。而不是研究细胞内模式的形成和肌动蛋白组装在细胞环境中，我想建立极化细胞形态发生的最低要求，通过自下而上的重组纯化的成分。虽然这个过程非常复杂，并且在活细胞中受到高度调控，但我们已经达到了一个点，在这个领域中，可以以这种方式解决一些选择性的相关问题。具体来说，我想了解（i）膜相关信号系统如何自组织成宏观空间模式，以及（ii）肌动蛋白细胞骨架如何利用膜极性在细胞的相对两端构建不同的结构。为此，我将结合联合收割机多蛋白重建人工膜与先进的荧光成像技术，并采用合成生物学方法。作为一个整体，这项工作有可能推进我们的细胞极性和形态发生的机制基础的系统生物化学水平的理解。

Living cells organize their interior in a non-random, polarized manner to carry out specialized biological functions. Cell polarity arises from a complex interplay between the plasma membrane, associated proteins and cytoplasmic molecules. In eukaryotic cells, symmetry is in most cases initially broken at the level of membrane-bound molecules such as phosphatidylinositol lipids and Rho-type GTPases. These conserved signaling hubs synergistically control cell morphogenesis and movement through the actin cytoskeleton. While many of the components of these intimately linked systems have been defined, very little is known about the biochemical mechanisms underlying cell polarity and shape changes. Instead of studying intracellular pattern formation and actin assembly in the cellular environment, I want to establish the minimal requirements for polarized cell morphogenesis through bottom-up reconstitution from purified components. While this process is very complex and highly regulated in living cells, we have reached a point in the field where a number of select, pertinent questions can be addressed in such a manner. Specifically, I want to understand (i) how membrane-associated signaling systems self-organize into macroscopic spatial patterns and (ii) how membrane polarity can be harnessed by the actin cytoskeleton to construct distinct structures at opposing ends of the cell. To this aim, I will combine multiprotein reconstitution on artificial membranes with advanced fluorescence imaging techniques and employ synthetic biology methods. As a whole, this work has the potential to advance our understanding of the mechanistic foundations of cell polarity and morphogenesis at the systems biochemistry level.