Vascular inflammation and neurotoxicity in aging brain

衰老大脑中的血管炎症和神经毒性

基本信息

批准号：
7474567
负责人：
PAULA GRAMMAS
金额：
$ 31.87万
依托单位：
TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-08-01 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7474567
关键词：
Address Affect Age Age-Months Aging Alzheimer&apos s Disease Animals Anti-Inflammatory Agents Anti-inflammatory Biochemical Blood Vessels Brain Brain Diseases CCL2 gene CXC Chemokines Cell Death Central Nervous System Diseases Cerebrum Clinical Defect Development Disease Disease Progression Enzyme-Linked Immunosorbent Assay Etiology Event Functional disorder Hyperhomocysteinemia Hyperlipidemia IL8 gene Immunohistochemistry In Vitro Inflammation Inflammatory Injury Interleukin-6 Laboratories Lesion Link Lipids Mediating Mediator of activation protein Modeling Molecular Nerve Degeneration Neurodegenerative Disorders Neurotoxins Northern Blotting Oxidative Stress Pathologic Pathology Patients Pharmaceutical Preparations Polymerase Chain Reaction Predisposition Proteins Rattus Reactive Oxygen Species Research Personnel Reverse Transcriptase Polymerase Chain Reaction Risk Factors Rodent Testing Time Tissues Tumor Necrosis Factor-alpha Work age related aged aging brain base chemokine cytokine human TNF protein in vivo insight juvenile animal neuron loss neurotoxic neurotoxicity novel prevent programs vascular inflammation

项目摘要

DESCRIPTION (provided by applicant): Despite the fact that many neurodegenerative diseases are age-related disorders, how aging predisposes the CNS to the development of neurodegenerative pathologies has not been adequately addressed. Numerous studies have documented an increase in inflammatory proteins in neurodegenerative diseases. However, whether age-related changes in inflammatory mediators are causally-linked to age-related disease progression is unknown. Our laboratory has shown that in Alzheimer's disease a pro-inflammatory cerebral vasculature releases neurotoxins and likely contributes to neuronal cell death. It is our hypothesis that age-related inflammatory changes in brain blood vessels contribute to age-related pathology in the brain. Because neuronal cell death is a central lesion in age-associated neurodegenerative diseases, we postulate a chain of events linking age-related increases in inflammation with vascular-mediated neuronal cell death. Aim 1- To determine if expression of inflammatory proteins increases in the cerebral vasculature with age. Fischer 344 rats at 6,12, 18, and 24 months of age are used to determine whether aging, in the absence of disease, affects vascular expression of inflammatory cytokines (IL-1beta, IL-6, IL-8, TNF-alpha) and chemokines (RANTES, MCP-1, MIP1-alpha). Inflammatory proteins are determined by ELISA, western and Northern blots, and real-time PCR and RT-PCR in isolated brain microvessels and by immunohistochemistry on tissue sections. Aim 2- To determine if age-related inflammatory changes are causally-linked to vascular mediated neuronal cell death. Our model predicts that in aging-vascular inflammation in the brain contributes to vascular-mediated neuronal cell death after injury. The cerebral microvasculature of Fischer 344 rats at 6,12,18, and 24 months is exposed to lipid or oxidative stress using both in vivo and in vitro injury models and vascular-mediated neuronal cell death assessed. Administration of anti-inflammatory drugs prior to injury is used to determine whether inhibiting inflammation prevents release of neurotoxic factors. These results would, for the first time, identify a mechanistic cascade linking age-related inflammatory changes to vascular mediated neuronal cell death. Results from this project could highlight a heretofore-unappreciated aspect of aging and suggest that approaches aimed at minimizing vascular inflammation and maintaining brain vascular function could be important for successful brain aging.

描述（由申请人提供）：尽管许多神经退行性疾病是与年龄有关的疾病，但衰老如何使CNS易于发育神经退行性病理的发展。许多研究表明，神经退行性疾病中炎症蛋白的增加。然而，尚不清楚与年龄相关的炎症介质的变化与年龄相关疾病的进展是否存在因果关系。我们的实验室表明，在阿尔茨海默氏病中，促炎的脑血管释放神经毒素，并可能导致神经元细胞死亡。我们的假设是，与年龄相关的脑血管炎症变化有助于大脑与年龄相关的病理。由于神经元细胞死亡是与年龄相关的神经退行性疾病的中心病变，因此我们假设一系列事件将与年龄相关的炎症与血管介导的神经元细胞死亡联系起来。目标1-确定炎症蛋白的表达是否随着年龄的增长而增加。 6,12、18和24个月大的Fischer 344只大鼠用于确定衰老（在没有疾病的情况下）是否会影响炎性细胞因子（IL-1Beta，IL-6，IL-6，IL-8，TNF-Alpha）的血管表达是否会影响衰老是否会影响衰老。炎性蛋白通过ELISA，西部和北印迹确定，以及分离的脑微血管中的实时PCR和RT-PCR以及组织切片的免疫组织化学。目标2-确定与年龄相关的炎症变化是否与血管介导的神经元细胞死亡有因果关系。我们的模型预测，在大脑衰老的血管炎症中，损伤后有助于血管介导的神经元细胞死亡。使用体内和体外损伤模型以及血管介导的神经元细胞死亡评估了菲舍尔344只大鼠的脑微脉管系统，并在6,12,18和24个月中暴露于脂质或氧化应激。施用抗炎药在受伤前的施用用于确定抑制炎症是否阻止了神经毒性因子的释放。这些结果将首次确定将与年龄相关的炎症变化与血管介导的神经元细胞死亡联系起来的机理级联反应。该项目的结果可能会突出迄今为止衰老的未经认可的方面，并建议旨在最大程度地减少血管炎症和维持脑血管功能的方法对于成功的大脑衰老可能很重要。