Dysbindin-Dependent Synaptic Vesicle Fusion Mechanisms

Dysbindin依赖性突触小泡融合机制

基本信息

批准号：
9566490
负责人：
Victor Faundez
金额：
$ 54.42万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-19 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9566490
关键词：
ANGPTL2 gene Actins Address Affect Alleles Behavior Biochemical Biochemical Genetics Biology Communication Complex DNA Sequence Alteration Defect Drosophila genus Endosomes Event Gene Mutation Genes Health Homeostasis Human Intervention Lead Learning Link Membrane Fusion Modeling Molecular Mutation N-ethylmaleimide-sensitive protein Neurodevelopmental Disorder Neurodevelopmental Impairment Neuromuscular Junction Neurons Organelles Orthologous Gene Pathway interactions Phenocopy Phenotype Physiology Play Predisposition Process Proteins Psyche structure Recycling Role SNAP receptor Schizophrenia Sensory Sorting - Cell Movement Susceptibility Gene Synapses Synaptic Vesicles Synaptic plasticity Testing Transgenic Organisms Vesicle gene product habituation loss of function loss of function mutation polymerization postsynaptic postsynaptic neurons predictive modeling presynaptic response reverse genetics scale up trafficking

项目摘要

How do mutations in genes implicated in human mental/neurodevelopmental disorders progressively scale up from a single molecular defect to protein networks (interactome), the physiology of the synapse, and behavior? We seek answers to this question as they hold promising explanatory and interventional power in neurodevelopmental disorders. We have chosen to address this question using the combined power of reverse genetics in Drosophila, on an experimentally defined dysbindin-SNARE machinery interaction. We evaluate mechanisms and phenotypic consequences of genetically manipulating the neurodevelopmental disorder pathway constituted by dysbindin NSF- and SNARE-dependent vesicle fusion. In this application, we will determine the functional consequences of genetically perturbing dysbindin-SNARE fusion mechanisms on the physiology of the Drosophila NMJ synapse and two forms of synaptic plasticity: presynaptic homeostatic plasticity and a simple form of learning, short-term olfactory habituation. We postulate that the dysbindin-SNARE machinery interactions are necessary for presynaptic endosome vesicle traffic to establish presynaptic homeostatic plasticity and olfactory habituation.

与人类精神/神经发育障碍有关的基因突变如何从单个分子缺损到蛋白质网络（Interactome），突触的生理和行为逐渐扩展？我们在神经发育障碍中拥有有希望的解释和介入能力时，我们寻求答案。我们选择使用果蝇中反向遗传学的综合能力来解决这个问题，这是在实验定义的Dysbindin-Snare机械相互作用上。我们评估了遗传操纵神经发育障碍途径的机制和表型后果，由dysbindin nsf和依赖性的囊泡融合构成。在此应用中，我们将确定遗传上扰动dydybindin-Snare融合机制对果蝇NMJ突触生理学的功能后果和两种形式的突触可塑性：突触前体内稳态可塑性和一种简单的学习形式，一种简单的学习形式。我们假设dysbindin-Snare机械相互作用对于突触前内体囊泡流量是必需的，以建立突触前的稳态可变性和嗅觉习惯。