STRUCTURAL STUDIES OF BOTULINUM NEUROTOXINS

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 肉毒神经毒素（BoNT）对人类构成生物危害，被疾病控制中心（CDC）列为A级生物恐怖主义威胁因子。它们由七种不同的血清型组成，称为BoNT/A-G。BoNT在神经肌肉接头（NMJ）处以高特异性结合，并且它们通过SNARE（可溶性N-乙基马来酰亚胺敏感性融合蛋白附着蛋白受体）的特异性蛋白水解损害含有乙酰胆碱的突触囊泡的胞吐作用，SNARE构成突触囊泡融合机制的一部分。随后，BoNT抑制运动神经元活动，从而抑制呼吸，导致呼吸停止。令人惊讶的是，BoNT的一些血清型不仅会使神经元麻痹，而且还会引起神经突损失并最终导致神经元凋亡（神经变性）。我们建议研究BoNT的作用机制，以更好地表征其在神经退行性变中的作用，并开发抑制剂来治疗和预防这种新形式的BoNT损伤。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Botulinum neurotoxins (BoNTs) pose a biological hazard to humans and are classified as Class-A bioterrorism threat agents by Centers for Disease Control (CDC). They are composed of seven different serotypes named BoNT/A-G. BoNTs bind with high specificity at neuromuscular junctions (NMJs) and they impair exocytosis of synaptic vesicles containing acetylcholine through specific proteolysis of SNAREs (soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptors), which constitute part of the synaptic vesicle fusion machinery. Subsequently, BoNTs inhibit motor neuron activity and thus breathing, resulting in respiratory arrest. Surprisingly, some serotypes of BoNT will not only paralyze neurons but also cause neurite loss and ultimately lead to neuronal apoptosis (neurodegeneration). We propose to study the mechanism of action of BoNTs in order to better characterize its role in neurodegeneration and to develop inhibitors to treat and prevent this new form of BoNT injury.