CELL SIGNALING AND ALZHEIMERS MITOCHONDRIAL DYSFUNCTION

细胞信号传导和阿尔茨海默病线粒体功能障碍

基本信息

批准号：
6430833
负责人：
GAUTAM N BIJUR
金额：
$ 4.2万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-02-01 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/6430833
关键词：
Alzheimer's disease DNA binding protein G protein antioxidants biological signal transduction disease /disorder etiology disease /disorder model enzyme activity free radical oxygen human tissue hybrid cells mitochondria phosphatidylinositols protein kinase C receptor coupling tissue /cell culture transcription factor

项目摘要

DESCRIPTION: (Applicant's abstract) There is mounting evidence that reactive oxygen intermediates (R0Is) my play a role in the etiology of Alzheimer's disease (AD). Although there are several endogenous sources of ROIs implicated in AD pathogenesis, this proposal will focus on ROIs produced due to mitochondrial dysfunction. To model this in tissue culture, we will used "cybrid" human neuroblastoma cells whose endogenous mitochondria have been replaced with mitochondria from patients with AD or matched controls. This proposal will address how the elevated levels of ROIs in AD cybrids affects cholinergic G-protein- coupled phosphoinositide (PI) signaling, protein kinase C (PKC) and extracellular signal regulated protein kinase (ERK) tyrosine phosphorylation and activation and transcription factor DNA binding. Our main hypothesis are that elevated ROIs will increase PKC and ERK tyrosine phosphorylation and activity and transcription factor activity and will attenuate responses to cholinergic receptor stimulation. Furthermore, AD cybrids will demonstrate increased sensitivity to the addition of oxidants and antioxidants compared with control cybrids. These studies will yield a clearer understanding of the effects of ROIs on signaling systems which may model critical alterations associated with AD.

描述：（申请人的摘要）越来越多的证据表明活性氧中间体（R0Is）在病因学中发挥作用阿尔茨海默病（AD）。尽管有多种内源性来源与 AD 发病机制有关的 ROI，该提案将重点关注 ROI 由于线粒体功能障碍而产生。在组织中对此进行建模培养中，我们将使用“cybrid”人类神经母细胞瘤细胞，其内源性线粒体已被替换为来自患有 AD 的患者或匹配的对照。该提案将解决如何 AD cybrids 中 ROI 水平升高影响胆碱能 G 蛋白耦合磷酸肌醇 (PI) 信号传导、蛋白激酶 C (PKC) 和细胞外信号调节蛋白激酶 (ERK) 酪氨酸磷酸化和激活以及转录因子 DNA 结合。我们的主要假设是，提高 ROI 将增加 PKC 和 ERK 酪氨酸磷酸化和活性以及转录因子活性并会减弱对胆碱能受体刺激的反应。此外，AD cybrids 将表现出对与对照杂种相比，添加了氧化剂和抗氧化剂。这些研究将使人们更清楚地了解投资回报率的影响信号系统可以模拟相关的关键改变与AD。