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Dysbindin and the Mechanisms Controlling Homeostatic Synaptic Plasticity

Dysbindin 和控制稳态突触可塑性的机制

基本信息

批准号：
8139972
负责人：
DION KAI DICKMAN
金额：
$ 8.76万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-10 至 2011-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8139972
关键词：
Area Binding Biochemical Biological Assay Biological Markers Calcium California Cells Commit Complex Data Defect Development Drosophila genus Electrophysiology (science)Environment Etiology Event Feedback Functional disorder Genes Genetic Screening Goals Homeostasis Homologous Gene Human Image Imagery Institution Invertebrates Laboratories Life Link Maps Mediating Mental disorders Mentors Modeling Molecular Monitor Mutation Nervous System Physiology Neuromuscular Junction Neurons Neurophysiology - biologic function Phase Physiological Presynaptic Terminals Process Property Protein Binding Proteins Regulation Research Research Personnel Role SNAP receptor SNAPIN gene San Francisco Schizophrenia Screening procedure Signal Transduction Susceptibility Gene Synapses Synaptic Transmission Synaptic Vesicles Synaptic plasticity System Testing Time Training Universities Vesicle aging brain base career fly mutant nervous system disorder neural circuit neuron development neurotransmission neurotransmitter release presynaptic protein protein interaction public health relevance response skills synaptic function trafficking

项目摘要

DESCRIPTION (provided by applicant): Dysbindin and the Mechanisms Controlling the Homeostatic Modulation of Presynaptic Neurotransmitter Release Nervous system function remains remarkably stable despite the many changes that occur during the development, maturation, and aging of the brain. There is increasing evidence that neurons are endowed with potent mechanisms that compensate for perturbations to their activity and maintain the stability of neural function within proper physiological ranges. Although these homeostatic properties have been demonstrated in a variety of systems from invertebrates to humans, the mechanisms that mediate these fundamental and complex processes are poorly understood. Using Drosophila as a model for homeostasis at the level of the synapse, we have recently demonstrated that the gene dysbindin is required for synaptic homeostasis. Interestingly, the human homolog of dysbindin (DTNBP1) has emerged as a primary susceptibility gene for schizophrenia. The overall objective of this proposal is to define the mechanisms through which Dysbindin modulates neural function and achieves the homeostatic control of synaptic stability. The initial aim will be to define the role of Snapin in synaptic function and homeostasis. Snapin has been shown to bind Dysbindin and separately to modulate the synaptic fusion machinery. Next, biochemical and live imaging approaches will be used to monitor and test the importance of the Snapin-Dysbindin interaction for the homeostatic modulation of presynaptic release. Finally, I will explore the role of other proteins that interact with Dysbindin and go on to search for new genes that are required for synaptic homeostasis. The training phase of this research will be performed at the University of California, San Francisco in the laboratory of Dr. Graeme Davis. In this environment at UCSF, I will enhance both my experimental skills as well as the skills necessary to become a successful independent researcher. My long term goal is to understand the molecular mechanisms that govern the homeostatic control of neural function and how dysfunction in this process may contribute to complex neurological and psychiatric disease. I am committed to researching these areas at an academic institution. Public Health Relevance: Dysbindin has emerged as a primary susceptibility gene for schizophrenia in humans. This proposal seeks to elucidate the role of Dysbindin in the homeostatic control of neural function and to search for new genes involved in this process. Together, these efforts have to potential to implicate synaptic homeostasis in the etiology of schizophrenia and other complex psychiatric diseases. PUBLIC HEALTH RELEVANCE: Dysbindin has emerged as a primary susceptibility gene for schizophrenia in humans. This proposal seeks to elucidate the role of Dysbindin in the homeostatic control of neural function and to search for new genes involved in this process. Together, these efforts have the potential to implicate defects in synaptic homeostasis as a plausible contributing factor in the etiology of schizophrenia and perhaps other complex psychiatric diseases.

尽管在大脑发育、成熟和衰老过程中发生了许多变化，但神经系统功能仍保持显著稳定。越来越多的证据表明，神经元具有强大的机制来补偿对其活动的干扰，并在适当的生理范围内维持神经功能的稳定性。尽管从无脊椎动物到人类的各种系统都证明了这些稳态特性，但介导这些基本和复杂过程的机制却知之甚少。使用果蝇作为突触水平的内稳态模型，我们最近证明了基因dysbinding是突触内稳态所必需的。有趣的是，dysbindin （DTNBP1）的人类同源基因已成为精神分裂症的主要易感基因。本提案的总体目标是确定Dysbindin调节神经功能和实现突触稳定性稳态控制的机制。最初的目的是确定Snapin在突触功能和体内平衡中的作用。Snapin已被证明与Dysbindin结合，并分别调节突触融合机制。接下来，生化和实时成像方法将用于监测和测试Snapin-Dysbindin相互作用对突触前释放的稳态调节的重要性。最后，我将探讨与Dysbindin相互作用的其他蛋白质的作用，并继续寻找突触内稳态所需的新基因。本研究的训练阶段将在加州大学旧金山分校Graeme Davis博士的实验室进行。在UCSF的这种环境中，我将提高我的实验技能以及成为一名成功的独立研究人员所需的技能。我的长期目标是了解控制神经功能稳态控制的分子机制，以及这一过程中的功能障碍如何导致复杂的神经和精神疾病。我致力于在学术机构研究这些领域。公共卫生相关性：异常结合蛋白已成为人类精神分裂症的主要易感基因。本研究旨在阐明Dysbindin在神经功能稳态控制中的作用，并寻找参与这一过程的新基因。总之，这些努力有可能在精神分裂症和其他复杂精神疾病的病因学中暗示突触内稳态。