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MECHANISM OF ACTION OF BOTULINUM NEUROTOXIN

肉毒神经毒素的作用机制

基本信息

批准号：
2750957
负责人：
Cara-Lynne Schengrund
金额：
$ 19.67万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-09-01 至 2000-07-31
项目状态：
已结题

项目摘要

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.

描述（来自申请人摘要）：虽然肉毒杆菌神经毒素（BTx）是迄今为止发现的毒性最大的生物毒素，它已被证明是治疗各种局灶性肌张力障碍的有用治疗剂。最近，BTx抑制神经递质释放的机制被通过其对“对接”所需的蛋白质的蛋白水解作用，突触囊泡的结构然而，有许多未回答的基本问题关于BTx作用机制的问题。的总体目标该建议是为了进一步确定其对细胞的粘附性及其在体内的作用，影响其突触体蛋白底物。这将通过确定1）聚类的数目和标识神经节苷脂-寡糖残基需要其最佳粘附，2）所需的重链羧基末端的精确区域对于其与神经节苷脂的粘附，3）神经节苷脂结合位点是否是其细胞粘附所需的唯一位点，以及4）BTxA的半衰期以及它们对SNAP-25蛋白水平的影响（SNAP-25是BTx的这两种血清型作用的对接组分）。这些问题的答案可以解释长期的影响所引起的 BTx，导致其更有效的临床使用，并建议可能的作为使用抗血清治疗接触肉毒梭菌或其神经毒素。