Leveraging the genetics and biochemistry of UNC-13 to uncover mechanisms driving neurotransmitter secretion

利用 UNC-13 的遗传学和生物化学揭示驱动神经递质分泌的机制

基本信息

批准号：
10749622
负责人：
Ziasmin Shahanoor
金额：
$ 4.77万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-17 至 2026-08-16
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10749622
关键词：
Automobile Driving Behavioral Binding Biochemical Biochemistry Brain Bypass C-terminal Caenorhabditis elegans Cell membrane Cells Chemicals Communication Complex Congenital musculoskeletal anomalies Data Docking Event Future Genetic Human Image Lead Lipid Binding Mediating Membrane Fusion Methods Modeling Monitor Mouse Protein Mutation Names Nervous System Physiology Neurons Neurotransmitters Orthologous Gene Paper Phenotype Point Mutation Presynaptic Terminals Process Proteins Proteomics Quality Control Regulation Research Role SNAP receptor Seizures Site Solid Synapses Synaptic Transmission Synaptic Vesicles Testing UNC13B gene Work developmental disease gain of function imaging approach in vivo evaluation in vivo imaging loss of function model organism molecular assembly/self assembly mutant nervous system disorder neurotransmitter release novel presynaptic prevent protein distribution synaptic function synaptotagmin syntaxin 1

项目摘要

PROJECT SUMMARY Communication between cells in the brain occurs predominantly via chemical secretion in neuronal specializations called presynaptic terminals where synaptic vesicles (SVs) fuse with the plasma membrane to release neurotransmitter molecules. These membrane fusion events are tightly controlled and modulated by key synaptic proteins such as the neuronal SNARE proteins as well as Munc13-1/UNC-13, Munc18-1/UNC-18, Complexin, and Synaptotagmin. Munc13-1 is major hub for every step in synaptic transmission. Moreover, mutations in the human UNC-13 ortholog are associated with severe neurological and developmental disorders. Importantly, the mechanisms underlying the various Munc13-1 functions are largely unknown. We recently characterized a novel domain at the C-terminus of Munc13-1 termed HC2M that plays a role in SV docking/priming, and mutations in this domain have a devastating impact on synaptic transmission and nervous system function in the model organism C. elegans. Using a combination of genetic, behavioral, imaging, and biochemical methods, we will investigate the role of UNC-13 in driving the assembly of the neuronal SNAREs, a critical first step in SV priming. This project will shed light on some of the enduring mechanistic mysteries underlying synaptic transmission.

项目摘要大脑中细胞之间的通信主要通过神经元中的化学分泌发生专门称为突触前末端，突触囊泡（SVS）与质膜融合释放神经递质分子。这些膜融合事件由密钥严格控制和调节突触蛋白，例如神经元snare蛋白以及munc13-1/unc-13，munc18-1/unc-18，复合蛋白和突触毒素。 MUNC13-1是突触传输的每个步骤的主要枢纽。而且，人类UNC-13直系同源物中的突变与严重的神经和发育障碍有关。重要的是，各种MUNC13-1功能的机制在很大程度上尚不清楚。我们最近在称为HC2M的Munc13-1的C末端表征了一个新的域，该结构域在SV中起作用对接/启动和该域中的突变对突触传播和神经的毁灭性影响模型有机体秀丽隐杆线虫中的系统功能。结合遗传，行为，成像和生化方法，我们将研究UNC-13在驱动神经元的组装中的作用，A SV启动的关键第一步。该项目将阐明一些持久的机械谜团基础突触传输。