Multi-Domain Sec14 Proteins and Developmentally Regulated Membrane Morphogenesis

描述（由申请人提供）：拟议研究的目的是对一类研究不足的蛋白质进行全面的功能分析：磷脂酰肌醇/磷脂酰胆碱转移蛋白（PITP）。类似Sec 14的阴谋集团包括 > 500种蛋白质，但仍然是一类研究很少的信号蛋白。这对于多结构域Sec 14-蛋白质尤其如此，因为这些蛋白质的表达限于高等真核生物，因此不易于使用遗传方法进行功能分析。我们最近发现，Sec 14-Escherulin和Sec 14-GOLD蛋白控制发育调节途径的极化膜贩运拟南芥。我们将利用拟南芥模型来确定Sec 14-Escherulin和Sec 14-GOLD蛋白如何执行其生物学功能。我们期望来自这些拟南芥研究的发现将直接翻译到哺乳动物系统，并且这些研究将澄清关于这种高等真核多结构域Sec 14蛋白的功能机制的基本上未研究的问题。从人类健康的角度来看，证据表明Sec 14样PITP调节磷脂介导的信号转导过程和多种细胞过程之间的界面，如膜运输，肌动蛋白组织，脂质信号传导，受体介导的信号传导和神经元功能。由于在高等真核生物中存在几种已知的导致神经病变和癌症的遗传性Sec 14样蛋白不足的情况，因此拟议的研究将提供新的和基本的信息，这些信息直接关系到多结构域Sec 14蛋白保护哺乳动物免受神经退行性和增殖性疾病的分子机制。

DESCRIPTION (provided by applicant): The objective of the proposed research is to undertake a comprehensive functional analysis of an underinvestigated class of proteins: the phosphatidylinositol/ phosphatidylcholine transfer proteins (PITPs). The Sec14-like cabal of the PITP ensemble consists of > 500 proteins, yet remains a poorly studied class of signaling proteins. This is particularly true for multi-domain Sec14-proteins because expression of these proteins is limited to higher eukaryotes and thus less easily amenable to functional analysis using genetic approaches. We recently discovered that Sec14-nodulin and Sec14-GOLD proteins control developmentally regulated pathways for polarized membrane trafficking in Arabidopsis. We will take advantage of the Arabidopsis model to determine how Sec14-nodulin and Sec14-GOLD proteins execute their biological functions. We expect the findings that come from these Arabidopsis studies will translate directly to mammalian systems, and that these studies will clarify essentially uninvestigated questions regarding the mechanism of function of such higher eukaryotic multi-domain Sec14 proteins. From the standpoint of human health, the evidence indicates Sec14-like PITPs regulate the interface between phospholipid-mediated signal transduction processes and diverse cellular processes such as membrane trafficking, actin organization, lipid signaling, receptor-mediated signaling, and neuronal function. As there are several known cases of inherited Sec14-like protein insufficiency in higher eukaryotes that result in neuropathies and carcinomas, the proposed studies will provide new and fundamental information with direct bearing on the molecular mechanisms by which multi-domain Sec14s proteins protect mammals from neurodegenerative and proliferative diseases.