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分子层膜上的前后运动。这种分子运动将与囊泡内的催化反应相结合，为传感和信号传递的新型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都是由脂质双分子层膜提供的区隔性引起的。这些膜形成细胞内部液体和外部介质之间的重要屏障。然而，细胞外分子，如激素、营养物质和病原体，可以通过跨膜蛋白在细胞膜上传递信号来改变细胞内的化学反应。囊泡具有与细胞相同的存储、放大、转导和交流信息的潜力，该提案旨在通过一种新的跨膜信号转导途径将外部分子识别事件与内部催化过程耦合起来，从而在完全合成的系统中释放这种未开发的能力。囊泡已经用于药物输送应用，但反应性囊泡的潜力巨大——那些能够以某种特定的和有针对性的方式对外部信号（如分子结合事件）发生反应的囊泡——可用于复杂的传感应用和靶向药物输送。双层膜提供的区隔性将内部和外部溶液分开，并允许内部和外部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发展是实现区隔化偶联化学的第一步，类似于在自然界中发现的复杂磷酸化级联。改变合成结构（如囊泡）的内部化学反应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（如生物学对弱分子信号的放大）在传感和诊断中有应用，或者在前体药物的催化活化中用于控释应用。此外，能够有效转导化学信息的多价囊泡将为构建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.