Lipid peroxidation in amyloid plaque formation

描述（由申请人提供）：这是一个指导研究科学家发展奖（K 01）的申请，以发展主要研究者在神经退行性疾病和氧化应激领域的研究事业。该奖项的目标是提供主要研究者的培训，使他能够成为神经变性和氧化应激领域的独立研究者，并在奖项结束时获得NIH资助。培训计划包括两个部分：教育/课程工作/会议和研究。以下是研究计划的摘要。 目前的研究表明，氧化应激（如脂质过氧化）与淀粉样蛋白沉积和斑块形成之间存在相关性。然而，缺乏直接证据表明氧化应激参与淀粉样斑块的形成。这项训练计划的研究将测试以下假设：脂质过氧化的改变可以影响A-β肽的沉积，并改变小鼠大脑中淀粉样蛋白斑块的水平。本研究将使用转基因和基因敲除小鼠模型来检验假设。将使用具有不同PHGPx（磷脂氢过氧化物谷胱甘肽过氧化物酶）水平的两种小鼠模型：Gpx 4敲除小鼠（低表达PHGPx）和Gpx 4转基因小鼠（过表达PHGPx）。PHGPx是由Gpx 4基因（谷胱甘肽过氧化物酶基因4）编码的一种独特的抗氧化防御酶，可直接对膜脂质过氧化物进行解毒，被认为是清除细胞膜脂质过氧化氢的最重要的酶。将这些小鼠与APP转基因小鼠（Tg 2576）杂交，产生PHGPx水平降低或升高的APP小鼠，APP转基因小鼠在脑中形成淀粉样蛋白斑块并显示认知缺陷。本研究主要有四个目的：（1）建立高表达PHGPx的转基因小鼠。(2)测定PHGPx水平降低或升高的APP小鼠脑中脂质过氧化水平。(3)测量具有降低或增加的PHGPx水平的APP小鼠脑中A-β 1 -42和A-β 1 -40肽的水平。(4)测量PHGPx降低或升高的APP转基因小鼠中淀粉样蛋白斑块的水平。这项研究将是第一次直接测试脂质过氧化作用在淀粉样斑块形成。

DESCRIPTION (provided by applicant): This is an application for Mentored Research Scientist Development Award (K01) to develop the Principal Investigator's research career in the area of neurodegeneration and oxidative stress. The goal of this award is to provide the Principal Investigator training that will allow him to become an independent investigator in the area of neurodegeneration and oxidative stress with a funded NIH grant by the end of the award. The training program consists of two parts: education/course work/meetings and research. The following is the summary of the research plan. Current research suggests a correlation between oxidative stress, such as lipid peroxidation, and amyloid deposition and plaque formation. However, direct evidence showing the involvement of oxidative stress in the formation of amyloid plaques is lacking. The research in this training program will test the following hypothesis: alterations in lipid peroxidation can affect the deposition of A-beta peptides and alter the levels of amyloid plaques in the brains of mice. Transgenic and knockout mouse models will be used in this study to test the hypothesis. Two mouse models with different PHGPx (phospholipid hydroperoxide glutathione-eroxidase) levels will be used: Gpx4 knockout mice (under-expressing PHGPx) and Gpx4 transgenic mice (over-expressing PHGPx). PHGPx, which is encoded by the Gpx4 gene (glutathione peroxidase gene 4), is a unique anti-oxidant defense enzyme that can detoxify membrane lipid peroxides directly and is considered to be the most important enzyme in removal of lipid hydroperoxides from ceil membranes. These mice will be crossed to APP transgenic mice (Tg2576), which develop amyloid plaques in the brain and show deficits in cognition, to produce APP mice with decreased or increased PHGPx levels. This study consists of four specific aims: (1) To produce transgenic mice that over express PHGPx. (2) To measure the levels of lipid-eroxidation in brains of APP mice with reduced or increased levels of PHGPx. (3) To measure the levels of A-beta'l-42 and A-beta1-40 peptides in brains of APP mice with reduced or increased levels of PHGPx. (4) To measure the levels of amyloid plaques in APP transgenic mice with reduced or increased PHGPx. This study will be the first direct test of the role of lipid peroxidation in amyloid plaque formation.