Sphingolipid/Sterol Microdomains and Neuronal Function

项目概述：本提案利用遗传工具来操纵富含鞘脂/固醇的液体有序微结构域的成分。神经元中的脂质微域定位神经传递所需的胞外机制，并定位和调节离子和神经递质通道。形成这些微结构域的脂质也与越来越多的神经退行性疾病有机械联系，包括鞘脂储存病、阿尔茨海默病和亨廷顿病。这些相同的脂质种类也与神经元中含有神经递质的囊泡的膜运输密切相关。驱动这一提议的基本假设是鞘脂/甾醇微结构域是细胞膜运输所必需的，这些微结构域的破坏是突触功能障碍和最终神经退行性变的潜在原因。利用果蝇的遗传模型系统，将对改变固醇和鞘脂代谢和运输的突变系进行神经元脂质组成、运输和微结构域形成的分析。此外，这些甾醇/鞘脂代谢突变体将被检测突触功能。使用遗传和药理学技术，神经退行性变由于在一系列神经元类型的脂质调节活动的破坏将被分析。利用果蝇将有助于快速发现神经元脂质微域组织和神经保护途径的新调控机制。与公共卫生的相关性：越来越多的人类神经退行性疾病以各种脂质积累/错误输送或脂质代谢失调为特征。这些脂质是重要的信号分子或突触囊泡周期的调节剂，对神经传递至关重要。脂质在突触功能和神经退行性疾病中的核心作用表明需要更好地了解神经元膜脂质的组成以及神经元中的脂质运输/信号传导。

DESCRIPTION (provided by applicant): Project Summary: This proposal utilizes genetic tools that manipulate components of sphingolipid/sterol rich liquid-ordered microdomains. Lipid microdomains in neurons localize exocytic machinery required for neurotransmission and localize and modulate ion and neurotransmitter channels. Lipids that form these microdomains are also mechanistically linked to a growing number of neurodegenerative diseases including, sphingolipid storage diseases, Alzheimer's Disease, and Huntington's Disease. These same lipid species are also intimately linked to membrane trafficking of neurotransmittor containing vesicles in neurons. The underlying hypothesis driving this proposal is that sphingolipid/sterol microdomains are required for membrane trafficking at the plasma membrane and disruption of these microdomains is an underlying cause of synaptic dysfunction and, ultimately, neurodegeneration. Utilizing the genetic model system of Drosophila, mutant lines that alter sterol and sphingolipid metabolism and transport will be assayed for neuronal lipid composition, trafficking and microdomain formation. Furthermore, these sterol/sphingolipid metabolism mutants will be assayed for synaptic function. Using genetic and pharmacalogical techniques, neurodegeneration due to disruption of lipid regulated activity in a range of neuron types will be assayed. Utilizing Drosophila will facilitate the rapid discovery of novel regulatory mechanisms of neuronal lipid microdomain organization and neuroprotective pathways. Relavance to public health: A growing number of human neurodegenerative diseases feature accumulation/mistrafficking of various lipid species or misregulation of lipid metabolism. These same lipids are important signaling molecules or regulators of the synaptic vesicle cycle essential for neurotransmission. The central role lipids execute in synaptic function and neurodegenerative diseases dictates the need to better understand neuronal membrane lipid composition as well as lipid trafficking/signaling in neurons.