Lipid peroxidation in amyloid plaque formation

淀粉样蛋白斑形成中的脂质过氧化

基本信息

批准号：
7227769
负责人：
QITAO RAN
金额：
$ 9.22万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-05-01 至 2008-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7227769
关键词：
3&apos Flanking Region 5&apos Flanking Region Affect Aging Alzheimer&apos s Disease Amyloid deposition Antioxidants Area Award Brain Brain region Cerebral cortex Cognition Deposition Disease Education Elderly Enzymes Etiology Event Excision Frequencies Funding Genes Glutathione Goals Grant Hippocampus (Brain)Human Hydrogen Peroxide Isoprostanes Knock-out Knockout Mice Lipid Peroxidation Lipid Peroxides Lipids Measures Membrane Membrane Lipids Mentored Research Scientist Development Award Methods Mus Nerve Degeneration Neurodegenerative Disorders Oxidative Stress Pathogenesis Pathologic Patients Peptides Phospholipids Play Polyunsaturated Fatty Acids Population Principal Investigator Protein Overexpression Research Research Personnel Role Secondary to Senile Plaques Staging Testing Tg2576 Tissues Training Training Programs Transgenic Mice Transgenic Organisms United States National Institutes of Health Work age group career glutathione peroxidase mouse model phospholipid-hydroperoxide glutathione peroxidase

项目摘要

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.

描述（由申请人提供）：这是指导研究科学家发展奖（K01）的申请，以开发主要研究者在神经退行性和氧化压力领域的研究生涯。该奖项的目的是提供首席调查员培训，该培训将使他成为神经退行性和氧化压力领域的独立调查员，并在奖励结束前获得资助的NIH赠款。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。当前的研究表明，氧化应激（例如脂质过氧化）与淀粉样蛋白沉积和斑块形成之间存在相关性。但是，缺乏表明氧化应激参与淀粉样斑块形成的直接证据。该培训计划中的研究将检验以下假设：脂质过氧化的改变会影响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。将使用两个具有不同PHGPX（磷脂氢过氧化酮 - 韧性酶）水平的小鼠模型：GPX4基因敲除小鼠（表达不足的PHGPX）和GPX4转基因小鼠（过表达PHGPX）。 PHGPX是由GPX4基因（谷胱甘肽过氧化物酶基因4）编码的，它是一种独特的抗氧化剂防御酶，可以直接排毒过氧化膜过氧化膜，被认为是去除脂质氢氧化物的脂质氢氧化物中最重要的酶。这些小鼠将越过APP转基因小鼠（TG2576），这些小鼠在大脑中发展淀粉样蛋白斑块并显示认知缺陷，以产生pHGPX水平降低或增加的APP小鼠。这项研究由四个特定目的组成：（1）产生超过phgpx的转基因小鼠。（2）测量具有降低或增加的PHGPX水平的APP小鼠大脑中脂质蠕虫化的水平。（3）测量APP小鼠大脑中A-Beta'l-42和A-Beta1-40肽的水平，PHGPX水平降低或增加。（4）测量降低或增加的PHGPX的APP转基因小鼠中淀粉样蛋白斑块的水平。这项研究将是对脂质过氧化在淀粉样菌斑形成中的作用的首次直接测试。