Mixed and active membranes

在这项提案中，我描述了我的计划，以解决我们对多组分、非平衡流体膜的理解面临的几个重要的公开问题。在生物学背景下，这些细胞通常与活细胞的细胞骨架相互作用。我将研究外力是如何引起膜微相分离的，例如，可能是由于耦合到活跃的细胞骨架而引起的。为了理解最近的数据，例如，对于局部膜扩散常数的较大变化，迫切需要这个模型。我还计划研究活细胞膜张力和压力的调节和瞬时适应。我将构建一个合适的非平衡模型，用于在膜和细胞骨架之间建立瞬时键，并利用这个模型来建立一个关于这些量的稳态和时间变化的自洽理论。锚定在细胞骨架上的分子马达产生的力作用于这些键。键的寿命取决于膜的顺应性，而膜的顺应性又取决于它的张力和压力，这种方式可以自我计算。细胞在体积或膜面积迅速变化后的瞬时反应，可以通过现代的微吸管或系绳拉实验来探测。因此，我们希望建立一个细胞膜的主动力学性质的理论。我还将致力于严格测试长期存在但未经检验的Saffman-Delbruck膜扩散理论。我将分析居里研究所巴塞罗教授团队的实验数据。这些正在进行的实验是由我们最近对圆柱形膜管上流动的理论分析所推动的，其中我们认为，管子半径在这种几何形状中的受控变化可能会对Saffman-Delbruck理论提供迄今提出的最具歧视性的测试。我还将研究FtsZ收缩环的组装和动力学。这种蛋白质是细菌中的微管蛋白类似物，它组装成纤维，在分裂的细菌细胞周围形成一个环。这一过程涉及分子力产生、纤维自组装、解聚和膜介导力，所有这些都是我拥有丰富专业知识的领域。最近的体外模型实验研究了FtsZ在产生膜变形中的作用。我们计划在膜泡中重复类似的实验，但增加了额外的重要分子成分，如FTSA，它在将FtsZ环与膜联系起来方面发挥着重要作用。对于产生受控薄膜变形的这些隔环的作用，一个可测试的物理模型在当代最有价值的领域中将是最有用的。人们希望这也可能具有药学上的相关性，例如在针对细胞分裂装置的新的抗菌治疗中。这项提议还有一个额外的因素，由于保密原因在这里没有包括在内。

In this proposal I describe my plan to attack several important open problems facing our understanding of multi-component, non-equilibrium fluid membranes. In a biological context these often interact with the cytoskeleton of a living cell. I will study how membrane microphase separation is induced by applied forces, such as might arise from coupling to the active cytoskeleton. This model is desperately needed to understand recent data, e.g. for large variations in the local membrane diffusion constant.I also plan to study the regulation and transient adaptation of the membrane tension and pressure of a living cell. I will construct an appropriate non-equilibrium model for the creation of transient bonds between the membrane and the cytoskeleton and use this to establish a self-consistent theory for the steady state, and time variation, of these quantities. Forces generated by molecular motors anchored to the cytoskeleton act on these bonds. The lifetime of the bonds depends on the membrane compliance, which in turn depends on it tension and pressure in a way that can be computed self-consistently. The transient response of the cell following rapid changes in volume or membrane area, can be probed by modern micropipette or tether-pulling experiments. We thereby hope to construct a theory for the active mechanical properties of the cell membrane.I will also work to rigorously test the long standing but untested Saffman-Delbruck theory for membrane diffusion. I will analyse experimental data from Prof Bassereau's group at the Institut Curie. These ongoing experiments have been motivated by our recent theoretical analysis of flows on cylindrical membrane tubes in which we suggest that the controlled variation of tube radius in this geometry may provide the most discriminatory test of the Saffman-Delbruck theory yet proposedI will also study the assembly and dynamics of the FtsZ contractile ring. This protein, a bacterial analogue of tubulin, assembles into fibers that form a ring around dividing bacterial cells. This process involves molecular force generation, fibre self assembly, depolymerisation and membrane-mediated forces, all of which are fields in which I have significant expertise. Very recently model in vitro experiments have studied the role of FtsZ in generating membrane deformation. We plan to repeat similar experiments in membrane vesicles but with the addition of additional vital molecular components, such as FtsA, which plays an important role in associating the FtsZ ring with the membrane. A testable physical model for the action of these dividing rings in generating controlled membrane deformation would be most useful in a field which is of the very highest contemporary interest. There is the hope that this may also have pharmaceutical relevance, e.g. in new antibacterial treatments that target the cell division apparatus.There is an additional element to this proposal which is not included here for reasons of confidentiality.