Vascular-Mediated Neuronal Cell Death Alzheimer's

血管介导的神经元细胞死亡阿尔茨海默病

• 批准号: 7467265
• 负责人: PAULA GRAMMAS
• 金额: $ 29.83万
• 依托单位: TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7467265
• 关键词: 1-Phosphatidylinositol 3-Kinase; Affect; Age; Alzheimer' s Disease; Amyloid beta-Protein; Angiogenesis Inhibitors; Angiogenic Factor; Angiogenic Proteins; Angiopoietin-2; Animal Experiments; Animal Model; Animals; Behavioral; Blood Vessels; Brain; Cerebrum; Characteristics; Clinical; Clinical Research; Data; Deposition; Development; Disease; Disease Marker; Disease Progression; Endothelial Cells; Endothelin-1; Epidemiologic Studies; Event; Extracellular Signal Regulated Kinases; Genes; Genome; Growth; Human; Hypoxia; Hypoxia Inducible Factor; Immunohistochemistry; Impaired cognition; In Vitro; Inflammation; Inflammatory; Integrins; Interleukin-1; Interleukin-6; Interleukin-8; Interleukins; JUN gene; Link; MAPK14 gene; Matrix Metalloproteinases; Measures; Mediating; Mitogen-Activated Protein Kinases; Modeling; Molecular; Molecular Profiling; Monocyte Chemoattractant Protein-1; Nitric Oxide; Pathogenesis; Pathology; Patients; Pharmaceutical Preparations; Phase III Clinical Trials; Phenotype; Phosphotransferases; Process; Proteins; Research Personnel; Signal Transduction; Stimulus; Testing; Thrombin; Transforming Growth Factors; Transgenic Mice; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Up-Regulation; Vascular Endothelial Growth Factors; Work; angiogenesis; cerebral hypoperfusion; clinically relevant; cognitive change; design; human TNF protein; human tissue; neuron loss; novel; novel therapeutics; programs; response; stress-activated protein kinase 1; therapeutic target; translational approach

DESCRIPTION (provided by applicant): Data are emerging to support the idea that factors and processes characteristic of angiogenesis are found in the Alzheimer disease (AD) brain. We have shown that in AD microvessels express or release many inflammatory, proangiogenic proteins. Despite increases in proangiogenic factors in the AD brain, evidence for increased vascularity is lacking. In our model we hypothesize that the angiogenic process does not progress to new vessel growth because an imbalance of pro- and anti-angiogenic factors results in aborted angiogenic signaling. In this project we test the hypothesis that AD microvessels express an anqiogenic phenotype and that this abnormal activation of brain endothelial cells is important for the development of AD pathology. Aim 1: To test the hypothesis that in AD brain microvessels become activated but fail to complete angiogenesis because an imbalance of pro- and anti-angiogenic factors results in aborted angiogenic signaling. Brain microvessels are isolated from AD patients, age-matched non-demented controls, and patients with inflammatory and non-inflammatory CMS disease. Isolated vessels are compared for expression of pro- and anti-angiogenic factors including thrombin, VEGF, endothelin-1 TGF-/0, nitric oxide, thrombospondin, and amyloid beta (A¿). The activities of signaling kinases phosphatidylinositol-3 kinase (PI3K)/Akt, p38 kinase, extracellular signal-regulated kinase (ERK), and c-Jun NH2-terminal kinase (JNK) are measured. Immunohistochemistry of brain sections is used to assess the spatial correlation of pro- and anti-angiogenic proteins with A/? deposition and AD pathology. Aim 2: To test the hypothesis that acquisition of the angiogenic phenotype contributes to the pathogenesis of AD pathology and cognitive impairment in animal models of AD. To determine the temporal association between acquisition of the angiogenic phenotype and the onset of disease, markers of angiogenesis are measured in isolated brain microvessels obtained from AD transgenic mice before the onset of cognitive changes and AD pathology and at several ages during disease progression. A causal link between the angiogenic phenotype and disease progression is evaluated using antiangiogenic drugs. Administration of these drugs to animals prior to the onset of behavioral changes and AD pathology will determine whether inhibiting the angiogenic phenotype affects the course of disease. Taken together, data from Aim 1 showing the clinical relevance of angiogenic changes in AD and results from Aim 2 demonstrating a causal link between the angiogenic phenotype and disease progression would argue strongly for a new therapeutic approach in AD. These results could be very exciting because the angiogenic brain endothelial cell is a novel, unexplored therapeutic target, and several antiangiogenic drugs are currently in use in Phase III clinical trials. Thus, clinical studies with angiogenesis inhibitors could be rapidly designed and implemented in AD patients.

描述（由申请人提供）：数据正在出现，以支持在阿尔茨海默病（AD）大脑中发现血管生成特征性因子和过程的想法。我们已经表明，在AD微血管表达或释放许多炎症，促血管生成蛋白。尽管AD脑中促血管生成因子增加，但缺乏血管分布增加的证据。在我们的模型中，我们假设血管生成过程不会进展到新血管生长，因为促血管生成因子和抗血管生成因子的不平衡导致血管生成信号传导中断。在这个项目中，我们测试的假设，AD微血管表达anqiogenic表型，这种异常激活的脑内皮细胞是重要的AD病理的发展。目标1：为了检验AD中脑微血管被激活但不能完成血管生成的假设，因为促血管生成因子和抗血管生成因子的不平衡导致血管生成信号的中止。从AD患者、年龄匹配的非痴呆对照以及患有炎性和非炎性CMS疾病的患者中分离脑微血管。比较分离的血管的促血管生成因子和抗血管生成因子的表达，所述促血管生成因子和抗血管生成因子包括凝血酶、VEGF、内皮素-1、TGF-β、一氧化氮、血小板反应蛋白和淀粉样蛋白β（A？）。测量信号激酶磷脂酰肌醇-3激酶（PI3K）/Akt、p38激酶、细胞外信号调节激酶（ERK）和c-Jun NH2-末端激酶（JNK）的活性。脑切片的免疫组织化学被用来评估促和抗血管生成蛋白与A/？沉积和AD病理学。目标二：在AD动物模型中验证血管生成表型的获得有助于AD病理和认知障碍的发病机制的假设。为了确定血管生成表型的获得与疾病发作之间的时间关联，在认知变化和AD病理学发作之前以及在疾病进展期间的几个年龄，在从AD转基因小鼠获得的分离的脑微血管中测量血管生成的标志物。使用抗血管生成药物评价血管生成表型和疾病进展之间的因果关系。在行为改变和AD病理学发作之前对动物施用这些药物将确定抑制血管生成表型是否影响疾病的进程。总之，来自目标1的数据显示了AD中血管生成变化的临床相关性，来自目标2的结果显示了血管生成表型与疾病进展之间的因果关系，这将有力地证明AD的新治疗方法。这些结果可能是非常令人兴奋的，因为血管生成脑内皮细胞是一种新的，未开发的治疗靶点，目前有几种抗血管生成药物正在III期临床试验中使用。因此，血管生成抑制剂的临床研究可以快速设计和实施在AD患者。