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

 描述（由申请人提供）：尽管存在遗传和环境干扰，但维持基线功能的能力对神经系统至关重要。在神经肌肉接头处，突触后受体功能的扰动导致突触前神经递质释放的增加，使肌肉兴奋恢复到基线水平。这个过程被称为突触稳态，从苍蝇到大鼠再到人类都是保守的。据推测，它在从自闭症到重症肌无力的神经系统疾病中发挥重要作用。这一过程的许多关键监管机构尚未确定。我们建议研究苍蝇II类PI 3-激酶，一种在初步实验中显示突触稳态所必需的脂质激酶。与更好地研究的I类和III类PI 3激酶不同，II类PI 3激酶在神经系统中还没有得到很好的理解。它们已被证明是重要的网格蛋白介导的内吞作用和从神经分泌细胞释放儿茶酚胺。通过本项目的两个目标，我们将描述II类PI 3-激酶在突触内稳态。首先，我们将测试的假设，苍蝇II类PI 3激酶是必要的，足以促进突触前释放。其次，我们将测试的假设，II类PI 3-激酶调节突触前释放通过改变容易释放池的囊泡。这些实验将使我们更好地了解突触稳态背后的机制，特别是脂质磷酸化在突触活动调节中的作用。这将为研究II类PI 3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系统疾病的靶点奠定基础。

 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.