Sphingolipid/Sterol Microdomains and Neuronal Function

描述（由申请人提供）：项目摘要：该提案利用遗传工具操纵富含鞘脂/甾醇的液体有序微区的组分。神经元中的脂质微区定位神经传递所需的胞吐机制，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（包括鞘脂贮积病、阿尔茨海默病和亨廷顿病）机械相关。这些相同的脂质种类也与神经元中含有囊泡的神经递质的膜运输密切相关。驱动这一提议的基本假设是鞘脂/固醇微结构域是质膜处的膜运输所需的，并且这些微结构域的破坏是突触功能障碍和最终神经变性的根本原因。利用果蝇的遗传模型系统，将测定改变固醇和鞘脂代谢和转运的突变株系的神经元脂质组成、运输和微区形成。此外，将测定这些固醇/鞘脂代谢突变体的突触功能。将使用遗传学和药理学技术，分析由于一系列神经元类型中脂质调节活性的破坏而导致的神经变性。利用果蝇将有助于快速发现神经元脂质微区组织和神经保护途径的新的调节机制。与公共卫生的关系：越来越多的人类神经退行性疾病的特征是各种脂质物质的积累/误分泌或脂质代谢的误调节。这些相同的脂质是神经传递所必需的突触囊泡周期的重要信号分子或调节剂。脂质在突触功能和神经退行性疾病中的中心作用决定了需要更好地理解神经元膜脂质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.