PTDINS TRANSFER PROTEIN FUNCTION AND NEURODEGENERATION

描述：拟议研究的目标是进行一项 详细分析了一项长期得到认可但调查明显不足的 蛋白质类：哺乳动物磷脂酰肌醇/磷脂酰胆碱 转运蛋白(PITPs)。这些无处不在的蛋白质催化运输 作为单体的磷脂酰肌醇或磷脂酰胆碱 体外膜双分子膜。只有在过去的七年里才有 关于这些细胞的生理功能的信息线索正在出现 然而，蛋白质。拟议的研究代表了一项全面和 多学科努力，旨在确定由执行的职能(S) PITPs在哺乳动物细胞中的表达，并确定它们之间的关系 磷脂结合/转运与哺乳动物PITP功能。个人目标 将包括使用转基因胚胎干细胞(ES)来 分析PITP在Reinoic酸诱导向成骨细胞分化中的作用 神经元谱系，以及PITP基因敲除小鼠的特征 确定由PITP不足引起的一般生理学。 这些研究将与新型突变PITPs(和天然的)的使用相结合 PITP变体)在互补性实验中 磷脂结合/转移特性与任何特定的 PITP的生理功能。以一种更直接的方法来定义 PITP功能，研究人员将表征发育完全的小鼠 诱导为中枢神经系统特异性PITP缺陷。最后， 他们将对不同的PITP亚型进行生化表征 将特定的生化特性与功能联系起来。班凯蒂斯家族 实验室处于独特的地位，可以建立这条调查路线作为 它已经开发出简便的遗传和生化系统，用于 提出了综合分析。 现有证据表明，PITP发挥着中心和以前的作用 磷脂介导的信号转导过程中未知的作用 它与蛋白质分泌等不同的细胞过程相互作用， 光转导和受体介导的信号传递。至少有两起案件 高等真核生物中遗传性PITP不足导致 神经变性，拟议的研究将提供新的和基础的 将直接与分子机制有关的信息，通过这些机制 PITPs保护哺乳动物的神经系统免受神经退行性疾病的侵袭。

DESCRIPTION: The objective of the proposed research is to undertake a detailed analysis of a long-recognized, but remarkably underinvestigated, class of proteins: the mammalian phosphatidylinositol/phosphatidylcholine transfer proteins (PITPs). These ubiquitous proteins catalyze the transport of either phosphatidylinositol or phosphatidylcholine, as monomers, between membrane bilayers in vitro. Only in the past seven years have any informative clues bee forthcoming as to the physiological function of these proteins, however. The proposed studies represent a comprehensive and multidisciplinary effort designed to identify the function(s) executed by PITPs in mammalian cells, and to determine the relationship between phospholipid binding/transfer and mammalian PITP function. Individual aims will include the use of genetically altered embryonic stem (ES) cells to dissect the role of PITP in reinoic acid-induced differentiation to the neuronal lineage, and the characterization of PITP knockout mice to determine the general physiology that results from PITP insufficiency. These studies will be coupled to the use of novel mutant PITPs (and natural PITP variants) in complementation experiments designed to address which phospholipid binding/transfer property is relevant to any particular physiological function of PITP. In a more directed approach for defining PITP function, the investigators will characterize fully developed mice induced for central nervous system-specific PITP deficiencies. Finally, they will biochemically characterize distinct PITP isoforms with a view toward linking specific biochemical properties with function. The Bankaitis laborator is in a unique position to establish this line of investigation as it has developed facile genetic and biochemical systems for the comprehensive analyse proposed. The available evidence suggests that PITPs play central and previously unrecognized roles in phospholipid-mediated signal transduction processes that interface with such diverse cellular processes as protein secretion, phototransduction, and receptor-mediated signalling. As at least two cases of inherited PITP insufficiency in higher eukaryotes result in neurodegeneration, the proposed studies will provide new and fundamental information that will bear directly on the molecular mechanisms by which PITPs protect the mammalian nervous system from neurodegenerative disease.