Long-term effects of botulinum neurotoxins on neuronal viability

肉毒杆菌神经毒素对神经元活力的长期影响

基本信息

批准号：
9249121
负责人：
Min Dong
金额：
$ 38.28万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9249121
关键词：
Acute Animals Attenuated Bacterial Toxins Bioterrorism Bontoxilysin Botulinum Toxin Type A Botulism Cause of Death Cell membrane Cleaved cell Clinical Clinical Data Communities Confusion Dangerousness Data Disease Dose Endocytosis Ensure Equilibrium Exocytosis Exposure to Family Food Poisoning Foundations GTP-Binding Protein alpha Subunits, Gs Genetic Polymorphism Genetic Variation Goals Human Human Genetics Image In Vitro Injection of therapeutic agent Ion Channel Label Link Long-Term Effects Maintenance Medical Membrane Molecular Motor Motor Neurons Mus Nerve Nerve Degeneration Neurons Paralysed Pathogenesis Patients Peptide Hydrolases Play Point Mutation Population Process Proteins Reporting Respiratory Muscles Rodent Rodent Model Role Rupture S-nitro-N-acetylpenicillamine Safety Signal Transduction Solid Synaptic Transmission Synaptic Vesicles Targeted Toxins Testing Therapeutic Therapeutic Uses Time Toxin Transgenic Mice base clinically relevant cytotoxic cytotoxicity embryonic stem cell in vivo killings member mouse model neuron loss novel programs public health relevance syntaxin 1

项目摘要

DESCRIPTION (provided by applicant): Botulinum neurotoxins are a family of seven bacterial toxins (BoNT/A-G) that cause the disease botulism in humans and animals. They target neurons and cleave host proteins required for synaptic vesicle exocytosis, thereby blocking synaptic transmission and paralyzing the hosts. This mode of action and its role in pathogenesis has been well established. Humans used to get exposed to BoNTs mainly via food poisoning, but significant changes have occurred in human- BoNT interactions. First, medical advances can now revive previously untreatable patients from acute BoNT actions. Second, BoNTs are utilized as therapeutics to target neurons via local injections over long periods of time. These changes have raised the critical need to examine the additional long-term consequences of exposure to BoNTs. Indeed, previous reports and our preliminary studies have revealed that a subset of BoNTs may induce degeneration of cultured rodent neurons in addition to blocking synaptic vesicle exocytosis. In Aim 1, we will examine whether BoNTs may induce degeneration of human neurons and in in vivo rodent models that mimic therapeutic applications. We will also investigate whether human genetic variations might render certain populations susceptible to potential cytotoxicity from the major therapeutic toxin BoNT/A. In Aim 2, we will examine our hypothesis that BoNTs induce neurodegeneration because their substrates play an essential role in maintaining the membrane balance at plasma membranes. Aim 1 will provide a solid foundation for establishing the potential clinical relevance. Aim 2 will provide a mechanistic understanding for BoNT cytotoxicity. Together, these studies will establish neuronal cytotoxicity as a "newly emerged" long-term consequence due to changes in BoNT-human interactions, with significant implications for understanding long-term effects of botulism in patients and for ensuring the safety of using BoNTs as therapeutic toxins.

描述（由申请人提供）：肉毒杆菌神经毒素是七个细菌毒素（BONT/A-G）的家族，引起人类和动物的疾病肉毒杆菌。它们靶向突触囊泡胞吐所需的神经元和裂解宿主蛋白，从而阻断突触传播并使宿主瘫痪。这种作用方式及其在发病机理中的作用已得到充分确立。人类过去主要通过食物中毒暴露于BONT，但人类相互作用发生了重大变化。首先，医疗进步现在可以通过急性骨动作来恢复以前无法治疗的患者。其次，将BONT用作长时间通过局部注射来靶向神经元的治疗剂。这些变化提出了检查暴露于BONT的额外长期后果的迫切需求。实际上，先前的报道和我们的初步研究表明，除了阻断突触小囊泡胞吐作用外，一部分BONT还可能引起培养的啮齿动物神经元的变性。在AIM 1中，我们将检查BONT是否可以诱导人类神经元的变性和模仿治疗应用的体内啮齿动物模型。我们还将研究人类遗传变异是否会使某些人群易受主要治疗性毒素BONT/A的潜在细胞毒性。在AIM 2中，我们将研究我们的假设，即BONT会诱导神经变性，因为它们的底物在维持质膜的膜平衡中起着至关重要的作用。 AIM 1将为建立潜在的临床相关性提供坚实的基础。 AIM 2将为BONT细胞毒性提供机械理解。总之，这些研究将建立神经元的细胞毒性，作为由于邦人类相互作用的变化而导致的“新出现”的长期后果，对理解肉毒杆菌主义对患者的长期影响以及确保将BONT作为治疗性毒素的安全性产生了重大影响。