Dysbindin and the Mechanisms Controlling Homeostatic Synaptic Plasticity

描述(由申请人提供)：结合障碍和控制突触前神经递质释放的动态平衡调节的机制尽管在大脑的发育、成熟和老化过程中发生了许多变化，但神经系统功能仍然非常稳定。越来越多的证据表明，神经元被赋予了强大的机制，可以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。虽然从无脊椎动物到人类的各种系统都证明了这些动态平衡特性，但调节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上的动态平衡模型，我们最近证明了基因异常结合素是突触动态平衡所必需的。有趣的是，人类的dybindin同源基因(DTNBP1)已经成为精神分裂症的主要易感基因。这项建议的总体目标是确定dybindin调节神经功能和实现突触稳定性的动态平衡控制的机制。最初的目标是确定Snapin在突触功能和动态平衡中的作用。已有研究表明，Snapin可以与异型结合蛋白结合，也可以单独调节突触融合机制。下一步，将使用生化和活体成像方法来监测和测试Snapin-dybindin相互作用对于突触前释放的动态平衡调节的重要性。最后，我将探索与dybindin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。这项研究的培训阶段将在加州大学旧金山分校格雷姆·戴维斯博士的实验室进行。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。我的长期目标是了解支配神经功能的动态平衡控制的分子机制，以及这一过程中的功能障碍如何可能导致复杂的神经和精神疾病。我致力于在一家学术机构研究这些领域。公共卫生相关性：dybindin已成为人类精神分裂症的主要易感基因。这项建议试图阐明异常结合素在神经功能的动态平衡控制中的作用，并寻找参与这一过程的新基因。总而言之，这些努力有可能将突触动态平衡与精神分裂症和其他复杂的精神疾病的病因学联系起来。 与公共卫生相关：在人类中，dybindin已成为精神分裂症的主要易感基因。这项建议试图阐明异常结合素在神经功能的动态平衡控制中的作用，并寻找参与这一过程的新基因。总而言之，这些努力有可能暗示突触稳态缺陷可能是精神分裂症和其他复杂精神疾病病因学的一个合理的贡献因素。

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.