Multi-Domain Sec14 Proteins and Developmentally Regulated Membrane Morphogenesis

描述(申请人提供)：拟议研究的目标是对一类未被研究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(PITPs)。PITP乐团中类似Sec14的阴谋集团包括 &gt；500蛋白，但仍是一类研究较少的信号蛋白。对于多结构域的Sec14-蛋白质来说尤其如此，因为这些蛋白质的表达仅限于高等真核生物，因此不太容易使用遗传方法进行功能分析。我们最近发现，Sec14-结节蛋白和Sec14-Gold蛋白控制着拟南芥极化膜运输的发育调控途径。我们将利用拟南芥模型来确定Sec14-结节蛋白和Sec14-Gold蛋白如何执行其生物学功能。我们希望来自这些拟南芥研究的结果将直接转化到哺乳动物系统，并且这些研究将澄清关于这种更高的真核多结构域Sec14蛋白的功能机制的基本上未被研究的问题。从人类健康的角度来看，有证据表明，Sec14类PITPs调节磷脂介导的信号转导过程与多种细胞过程之间的接口，如膜运输、肌动蛋白组织、脂信号、受体介导的信号和神经元功能。由于在高等真核生物中有几个已知的遗传性Sec14样蛋白缺乏导致神经疾病和癌症，拟议的研究将提供新的基础信息，直接关系到多结构域Sec14s蛋白保护哺乳动物免受神经退行性疾病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.