Functional Analysis of SV2 by Targeted Gene Disruption

通过靶向基因破坏对 SV2 进行功能分析

• 批准号: 7241506
• 负责人: Sandra M Bajjalieh
• 金额: $ 32.34万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7241506
• 关键词: Address; Age; Binding; Biochemical Pathway; Biological; Budgets; CCL4 gene; Calcium; Cell membrane; Cells; Chromaffin Cells; Chromosome Pairing; Defect; Dependence; Disease; Disruption; Docking; Electroretinography; Endocytosis; Event; Exhibits; Funding; Gene Targeting; Glycoproteins; Goals; Heterozygote; Hippocampus (Brain); Knockout Mice; Learning; Maintenance; Masks; Measures; Mediating; Mental disorders; Molecular; Molecular Neurobiology; Morphology; Mus; Mutate; Mutation; Neurons; Neurotransmitters; Phenotype; Physiologic pulse; Play; Probability; Process; Protein Isoforms; Protein Overexpression; Proteins; Pulse taking; Rate; Research Personnel; Retina; Retinal Degeneration; Role; Seizures; Semliki forest virus; Series; Site-Directed Mutagenesis; Synapses; Synaptic Transmission; Synaptic Vesicles; Testing; Vesicle; Work; addiction; base; cell type; experience; nervous system disorder; neurotransmission; neurotransmitter release; programs; protein expression; research study; ribbon synapse; size; synaptotagmin; synaptotagmin II; tool; transmission process

DESCRIPTION (provided by applicant): Determining the molecular events that produce and regulate the release of neurotransmitters is one of the central goals of molecular neurobiology. Defining these events, and how they are altered with experience and in disease, will provide an understanding of normal processes such as learning and serve as the biological basis for developing new therapies for mental illness, neurological disorders and addiction. The work proposed here addresses the function of Synaptic Vesicle Protein 2 (SV2), a glycoprotein constituent of all neurotransmitter-containing (synaptic) vesicles. In the last funding period we demonstrated that Synaptic Vesicle Protein 2 (SV2) is an essential modulator of neurotransmission. Loss of SV2A reduces neurotransmission in hippocampal and cortical neurons, and reduces the size of the readily releasable pool of vesicles in chromaffin cells. Reduced neurotransmission is not due to morphological changes or to a decrease in morphologically "docked" synaptic vesicles. Together these results suggest that SV2 is a positive modulator of vesicle priming that acts after vesicle attachment at the plasma membrane. We propose to use SV2 knockout mice to determine SV2's molecular function in fast neurotransmission and to resolve differences in isoform functioning. Our specific aims are: 1. To determine how neurotransmission is altered in cultured hippocampal neurons from SV2 KOs. 2. To use exogeneous protein expression in hippocampal neurons to test hypotheses of SV2 function. 3. To test the hypothesis that SV2B plays a crucial role in ribbon synapse maintenance and/or functioning.

描述（由申请人提供）：确定产生和调节神经递质释放的分子事件是分子神经生物学的中心目标之一。定义这些事件，以及它们如何随着经验和疾病而改变，将提供对学习等正常过程的理解，并为开发治疗精神疾病、神经障碍和成瘾的新疗法提供生物学基础。