Controlling Membrane Translocation for Artificial Signal Transduction

该提案的目的是开发化学方法来控制分子在脂质双层膜上的前后运动。这种分子运动将与囊泡内的催化反应相结合，为一类新的传感和信号传导化学系统开辟了道路。复杂生物系统的许多独特性质和功能来自脂质双层膜提供的区室化。这些膜在细胞的内部液体和外部介质之间形成重要的屏障。然而，细胞外分子，如激素，营养素和病原体，可以通过跨膜蛋白质跨越细胞膜发出信号来改变细胞内化学。囊泡有潜力以与细胞相同的方式存储，放大，储存和传递信息，该提案旨在通过将外部分子识别事件与内部催化过程通过新型跨膜信号转导途径耦合，在完全合成的系统中解锁这种未开发的能力。囊泡已经用于药物递送应用，但响应性囊泡具有巨大的潜力-那些可以以某种特定和靶向方式对外部信号（如分子结合事件）反应的囊泡-可用于复杂的传感应用和靶向药物递送。由双层膜提供的区室化将内部和外部溶液分开，并允许内部和外部的不相容的化学过程和网络独立共存。促进跨膜信号传导的合成结构的开发是实现区室化偶联化学的第一步，类似于自然界中发现的复杂磷酸化级联。改变合成构建体（如囊泡）的内部化学性质以响应其外部环境的能力将提供新的机会：将外部信号与内部催化过程耦合（如生物学用于放大弱分子信号）可应用于传感和诊断，或用于控制释放应用的前药的催化活化。此外，能够有效转导化学信息的多价囊泡将为构建用于与细胞系统通信的生物相容性界面提供平台。

The aim of the proposal is to develop chemical methods for controlling the motion of molecules backwards and forwards across lipid bilayer membranes. This molecular motion will be coupled to catalytic reactions inside vesicles, opening the way to a new class of chemical systems for sensing and signalling. Many of the unique properties and functions of complex biological systems arise from the compartmentalisation afforded by lipid bilayer membranes. These membranes form an important barrier between the cell's internal fluid and the external medium. However, extracellular molecules, such as hormones, nutrients and pathogens, can change the intracellular chemistry by signalling across the cell membrane via membrane-spanning proteins. Vesicles have the potential to store, amplify, transduce and communicate information in the same way as cells do, and this proposal aims to unlock this untapped capability in entirely synthetic systems, by coupling an external molecular recognition event with an internal catalytic process via a novel transmembrane signal transduction pathway. Vesicles are already used in drug-delivery applications, but there is huge potential for responsive vesicles - those that can react in some specific and targeted way to an external signal such as a molecular binding event - which could be used in sophisticated sensing applications and targeted drug delivery. The compartmentalisation afforded by the bilayer membrane separates the inside and outside solutions and allows otherwise incompatible chemical processes and networks on the interior and exterior to co-exist independently. The development of synthetic constructs that facilitate transmembrane signalling is the first step towards realising compartmentalised-coupled chemistry, analogous to the complex phosphorylation cascades found in Nature. The ability to change the internal chemistry of a synthetic construct, such as a vesicle, in response to its external environment will offer new opportunities: coupling the external signal to an internal catalytic process (as biology does for amplification of weak molecular signals) has applications in sensing and diagnostics, or in the catalytic activation of a pro-drug for controlled-release applications. Furthermore, multivalent vesicles that are capable of efficient transduction of chemical information will provide a platform for the construction of biocompatible interfaces for communication with cellular systems.