MECHANISM OF ACTION OF BOTULINUM NEUROTOXIN

描述(摘自申请者摘要)：肉毒杆菌神经毒素(BTX) 是到目前为止发现的最毒的生物毒素，它已经证明 是治疗各种局灶性肌张力障碍的有效药物。 最近，BTX抑制神经递质释放的机制是 这是通过它对“对接”所需蛋白质的蛋白质分解作用而显示的。 突触小泡。然而，有许多尚未回答的基本问题 关于BTX作用机制的问题。总的目标是 这一建议是为了进一步定义其在细胞上的黏附和体内的 对其突触体蛋白底物的影响。这将通过以下方式实现 确定1)集群的数量和身份 神经节苷脂-低聚糖残基是其最佳黏附所需，2) 所需的重链的羧基末端半部分的精确区域 对于其对神经节苷脂的黏附，3)神经节苷脂结合部位 是其细胞黏附所需的唯一部位，以及4)BTxA的半衰期 和BTxE体内表达及其对SNAP-25蛋白水平的影响 (Snap-25是这两种BTX血清型作用的对接组件)。 对这些问题的回答可能会解释 BTX，导致其更有效的临床应用，并建议可能的 可替代抗血清用于治疗以下个人 接触肉毒梭菌或其神经毒素。

DESCRIPTION (from applicant's abstract): While botulinum neurotoxin (BTx) is the most poisonous biological toxin identified so far, it has proven to be a useful therapeutic agent for the treatment of various focal dystonias. Recently, the mechanism by which BTx inhibits neurotransmitter release was shown to be by its proteolytic action on a protein needed for the "docking" of synaptic vesicles. There are however, many unanswered fundamental questions about the mechanism of action of BTx. The overall objective of this proposal is to further define its adherence to cells and its in vivo effect on its synaptosomal protein substrate. This will be accomplished by determining 1) the number and identity of clustered ganglioside-oligosaccharide residues needed for its optimum adherence, 2) the precise region of the carboxy-terminal half of the heavy chain needed for its adherence to gangliosides, 3) whether the ganglioside binding site is the only site needed for its cell adherence, and 4) the half-life of BTxA and BTxE in vivo, as well as their effect on the level of SNAP-25 protein (SNAP-25 is the docking component acted upon by these two serotypes of BTx). Answers to these questions may explain the long-lasting effects induced by BTx, result in its more effective clinical use, and suggest a possible alternative to the use of antiserum for the treatment of individuals that come into contact with Clostridium botulinum or its neurotoxin.