Dysbindin and the Mechanisms Controlling Homeostatic Synaptic Plasticity

项目摘要 障碍结合素与突触前平衡调节的调控机制 神经递质释放 神经系统功能仍然非常稳定，尽管在此期间发生了许多变化 大脑的发育、成熟和老化。越来越多的证据表明神经元被赋予了 有效的机制来补偿对其活动的扰动并维持神经的稳定性 在适当的生理范围内发挥作用。尽管这些动态平衡特性已经在 从无脊椎动物到人类的各种系统，调节这些基本和 人们对复杂的过程知之甚少。用果蝇作为体内稳态的模型 突触，我们最近证明了基因结合障碍是突触动态平衡所必需的。 有趣的是，人类的dybindin同源物(DTNBP1)已经成为一种主要的易感基因 精神分裂症。这项提案的总体目标是定义绑定障碍的机制 调节神经功能，实现突触稳定性的动态平衡控制。 最初的目标是确定Snapin在突触功能和动态平衡中的作用。Snapin有 研究表明，它们可以与异型结合蛋白结合，也可以单独调节突触融合机制。接下来，生物化学 并将使用实时成像方法来监测和测试管理单元结合障碍的重要性 突触前释放的动态平衡调节的相互作用。最后，我将探讨其他角色的作用 与dybindin相互作用并继续寻找突触所需的新基因的蛋白质 动态平衡。这项研究的培训阶段将在加州大学旧金山分校进行 弗朗西斯科在格雷姆·戴维斯博士的实验室里。在加州大学旧金山分校的这种环境下，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。我的龙 学期目标是了解支配神经功能内稳态控制的分子机制。 以及这一过程中的功能障碍可能会如何导致复杂的神经和精神疾病。我是 致力于在学术机构研究这些领域。

Project Summary 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.