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

基本信息

批准号：
8068745
负责人：
PAULA GRAMMAS
金额：
$ 28.39万
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：
1999
资助国家：
美国
起止时间：
1999-09-30 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8068745
关键词：
1-Phosphatidylinositol 3-Kinase Affect Age Alzheimer&apos 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 Genes 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 Up-Regulation Vascular Endothelial Growth Factors Work angiogenesis cerebral hypoperfusion clinically relevant cognitive change design genome-wide human tissue neuron loss novel novel therapeutic intervention programs response stress-activated protein kinase 1 therapeutic target translational approach

项目摘要

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）：正在出现的数据支持这样的观点，即在阿尔茨海默病（AD）大脑中发现了血管生成的特征性因子和过程。我们已经表明，在AD微血管中表达或释放许多炎症性促血管生成蛋白。在 AD 大脑中的促血管生成因子中，缺乏血管生成增加的证据，在我们的模型中，我们发现血管生成过程不会进展为新血管生长，因为促血管生成因子和抗血管生成因子的不平衡会导致中止。在这个项目中，我们测试了这样的假设：AD 微血管表达一种血管生成表型，并且脑内皮细胞的这种异常激活对于 AD 病理学的发展很重要。无法完成血管生成，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止。从 AD 患者、年龄匹配的非痴呆对照和患者中分离出脑微血管。比较分离的血管与炎症和非炎症 CMS 疾病的促血管生成因子和抗血管生成因子的表达，包括凝血酶、VEGF、内皮素-1 TGF-/0、一氧化氮、血小板反应蛋白和淀粉样蛋白 (A¿使用脑切片的免疫组织化学测定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。评估促血管生成蛋白和抗血管生成蛋白与 A/? 沉积和 AD 病理学的空间相关性。血管生成表型有助于 AD 动物模型中 AD 病理学和认知障碍的发病机制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，在从 AD 转基因小鼠获得的分离脑微血管中测量血管生成标记。在行为改变和 AD 病理发生之前，使用抗血管生成药物来评估血管生成表型和疾病进展之间的因果关系。无论综上所述，目标 1 的数据显示了 AD 中血管生成变化的临床相关性，目标 2 的结果证明了血管生成表型与疾病进展之间的因果关系，这将为新的治疗方法提供支持。这些结果可能非常令人兴奋，因为血管生成脑内皮细胞是一种新颖的、未经探索的治疗靶点，并且目前有几种抗血管生成药物正在用于血管生成的临床研究。抑制剂可以在 AD 患者中快速设计和实施。