Dysbindin-Dependent Synaptic Vesicle Fusion Mechanisms

Dysbindin依赖性突触小泡融合机制

• 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
• 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

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一分子缺陷逐渐扩大到蛋白质网络（相互作用组）、突触生理学和行为？我们寻求这个问题的答案，因为它们在神经发育障碍中具有很好的解释和干预能力。我们选择在果蝇中使用反向遗传学的组合力量来解决这个问题，实验定义了dysbindin-SNARE机制相互作用。我们评估机制和表型的后果遗传操纵的神经发育障碍的dysbindin NSF和SNARE依赖性囊泡融合构成的途径。在本申请中，我们将确定遗传干扰dysbindin-SNARE融合机制对果蝇NMJ突触生理学和两种形式的突触可塑性的功能后果：突触前稳态可塑性和一种简单的学习形式，短期嗅觉习惯化。我们假设，dysbindin-SNARE机制的相互作用是必要的突触前内体小泡交通建立突触前稳态可塑性和嗅觉习惯。