Dysbindin and the Mechanisms Controlling Homeostatic Synaptic Plasticity

项目摘要 Dysbindin及其控制突触前稳态调节的机制 神经递质释放 神经系统的功能保持非常稳定，尽管有许多变化，发生在 大脑的发育、成熟和衰老。越来越多的证据表明，神经元具有 有效的机制，以补偿扰动其活动和维持稳定的神经 在适当的生理范围内发挥作用。虽然这些自我平衡的特性已经在 从无脊椎动物到人类的各种系统，介导这些基本和 复杂的过程知之甚少。使用果蝇作为模型的稳态水平的 突触，我们最近已经证明了基因dysbindin是突触稳态所必需的。 有趣的是，dysbindin（DTNBP 1）的人类同源物已经成为Dysbindin的主要易感基因。 精神分裂症该提案的总体目标是确定Dysbindin通过其作用机制。 调节神经功能并实现突触稳定性的稳态控制。 最初的目标是确定Snapin在突触功能和稳态中的作用。Snapin有 已显示结合Dysbindin并分别调节突触融合机制。接下来，生物化学 和实时成像方法将用于监测和测试Snapin-Dysbindin的重要性， 突触前释放的稳态调节的相互作用。最后，我将探讨其他人的作用。 与Dysbindin相互作用的蛋白质，并继续寻找突触所需的新基因。 体内平衡本研究的培训阶段将在旧金山的加州大学进行 弗朗西斯科在格雷姆·戴维斯博士的实验室。在UCSF的这个环境中，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。我漫长 本学期的目标是了解支配神经功能稳态控制的分子机制 以及这个过程中的功能障碍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.