Developing novel inhibitors of unconventional secretion based on Botulinum based therapeutics

非常规分泌是一个基本的细胞过程，不仅支持正常生理，而且是慢性炎症和癌症的关键驱动因素。目前，我们对这一过程的分子和机理了解有限。本项目的目的是利用肉毒杆菌为基础的分子来阐明SNARE蛋白在非常规分泌中的作用。从长远来看，这个项目所产生的知识将为开发这种途径的新型抑制剂提供一个平台。梭菌神经毒素是由厌氧细菌如肉毒梭菌产生的。每个毒素分子都有一个高度保守的锌依赖蛋白酶结构域，该结构域特异性地切割SNARE蛋白，这是细胞内运输和囊泡融合所需的分子家族。该项目将利用一个新的毒素分子库来鉴定和表征SNARE蛋白在生物发生和非传统分泌载体与细胞表面融合中的作用。

Unconventional secretion is a fundamental cellular process which not only underpins normal physiology but is a key driver in chronic inflammation and cancer. At present we have a limited molecular and mechanistic understanding of this process. The aim of this project is to use Botulinum based molecules to elucidate the role of SNARE proteins in unconventional secretion. The knowledge generated from this project in the longer term will provide a platform for the development of novel inhibitors of this pathway.Clostridial neurotoxins are produced by anaerobic bacteria such as Clostridium botulinum. Each toxin molecule has a highly conserved zinc-dependent protease domain that specifically cleaves SNARE proteins, a family of molecules required for intracellular trafficking and vesicle fusion. This project will make use of a library of novel toxin molecules to identify and characterise the role of SNARE proteins in the biogenesis and fusion of unconventional secretory carriers with the cell surface.