Characterization of Class II PI3-kinase as a homeostatic synaptic plasticity gene

 描述(由申请人提供)：在遗传和环境扰动的情况下保持基线功能的能力对神经系统是必不可少的。在神经肌肉交界处，突触后受体功能的扰动导致突触前神经递质释放增加，使肌肉兴奋恢复到基线水平。这一过程被称为突触内稳态，从苍蝇到大鼠再到人类都是如此。据推测，它在从自闭症到重症肌无力等神经系统疾病中发挥着重要作用。这一过程的许多关键监管机构尚未确定。我们建议进行研究，以确定Fly-Class II PI3-Kinase的特征，这是一种在初步实验中被证明是突触内稳态所必需的脂酶。与研究较好的第I类和第III类PI3-激酶不同，第II类PI3-激酶在神经系统中没有得到很好的理解。它们被证明是重要的网状蛋白介导的内吞作用和儿茶酚胺从神经分泌细胞释放。通过这个项目的两个目标，我们将表征突触内稳态中的II类PI3-激酶。首先，我们将检验这一假设，即Fly Class II PI3-Kinase是促进突触前释放的必要和充分条件。其次，我们将检验这一假说，即II类PI3-激酶通过改变容易释放的囊泡池来调节突触前释放。这些实验将使我们更好地了解突触动态平衡背后的机制，特别是脂质磷酸化在突触活性调节中的作用。它将为研究第二类PI3-激酶作为治疗自闭症、阿尔茨海默病和重症肌无力等毁灭性神经疾病的靶点提供基础。

 DESCRIPTION (provided by applicant): The ability to maintain baseline function despite genetic and environmental perturbation is essential for the nervous system. At the neuromuscular junction, a perturbation to post-synaptic receptor function results in an increase of presynaptic neurotransmitter release, returning muscle excitation to baseline levels. This process is known as synaptic homeostasis and it is conserved from the fly to rat to human. It is hypothesized to play an important role in neurological diseases from autism to myasthenia gravis. Many key regulators of this process have yet to be identified. We propose research to characterize the fly class II PI3-kinase, a lipid kinase shown in preliminary experiments to be necessary for synaptic homeostasis. Unlike the better studied class I and class III PI3- kinases, class II PI3-kinases are not well understood in the nervous system. They have been shown to be important for clathrin mediated endocytosis and catecholamine release from neurosecretory cells. Through the two aims of this project, we will characterize the class II PI3-kinase in synaptic homeostasis. First, we will test the hypothesis that the fly class II PI3-kinase is necessary and sufficient for facilitating presynaptic release. Second, we will test the hypothesis that the class II PI3-kinase modulates presynaptic release by altering the readily releasable pool of vesicles. These experiments will allow us to better understand the mechanisms behind synaptic homeostasis, especially the role of lipid phosphorylation in the modulation of synaptic activity. It will provide the groundwork for studying class II PI3-kinases as therapeutic targets fr devastating neurologic diseases like autism, Alzheimer's disease, and myasthenia gravis.