Human vascular model to study Alzheimer's Disease
研究阿尔茨海默病的人体血管模型
基本信息
- 批准号:8923141
- 负责人:
- 金额:$ 15.31万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-09-15 至 2017-04-30
- 项目状态:已结题
- 来源:
- 关键词:AbdomenAdipose tissueAdvanced Glycosylation End ProductsAdverse effectsAlzheimer&aposs DiseaseAmyloidAmyloid beta-ProteinAmyloidosisAnimal ModelAutopsyBiologyBlood - brain barrier anatomyBlood VesselsBrainCadaverCerebrumClinical TrialsCoronaryDataDepositionDevelopmentDiabetes MellitusDiseaseEarly treatmentEndotheliumExposure toFunctional disorderFutureGlucoseGoalsHealthHumanHyperglycemiaHyperlipidemiaHypertensionInflammatoryInjuryInterventionKnowledgeLeadLifeMeasuresMicrovascular DysfunctionModelingNF-kappa BOrgan DonorOxidative StressPalmitic AcidsPathologicPathologyPathway interactionsPerfusionPeripheralProcessProteinsReceptor ActivationResearchRoleSaturated Fatty AcidsSignal TransductionSmooth MuscleStagingTestingTherapeuticTissue ModelTissuesToxic effectTransgenic MiceValidationVascular Diseasesarteriolebasecardiovascular risk factorcerebral hypoperfusioncytokinedisease stressorendothelial dysfunctionhuman tissueinsightmild cognitive impairmentnovelnovel therapeutic interventionprogramsprotein misfoldingresearch studyresponsesuccessvascular inflammation
项目摘要
DESCRIPTION (provided by applicant): Vascular disease and cardiovascular risk factors (diabetes, hyperlipidemia and hypertension) are strongly associated with Alzheimer's disease (AD) yet the mechanisms by which they lead to AD remain unknown. It is now well-recognized that vascular dysfunction leading to cerebral hypo perfusion and impaired blood brain barrier function occur early in AD and has a central role in early pathophysiology. Critical obstacles in AD research include the lack of knowledge of how cardiovascular risk factors contribute to AD or modulate Aß injury, and the lack of a human tissue model to study early vascular disease in AD. Our preliminary data show the feasibility of using ex-vivo leptomeningeal arterioles isolated by rapid autopsy from organ donors to study micro vascular response to Aß and cardiovascular risk factors. Our overall goal is to identify key mechanisms underlying Aß -induced micro vascular injury and systematically study how cardiovascular risk factors modulate Aß effects on endothelial function, oxidative stress and vascular inflammation. We hypothesize that Aß induces endothelial dysfunction and vascular inflammation through oxidative stress and activation of receptor for advanced glycation end products (RAGE) and nuclear factor kappa B (NF-KB) signaling, and hyperglycemia (HG) and palmitic acid (PA) will exacerbate Aß vascular toxicity by modulating these pathways in cerebral and peripheral adipose arterioles. In Aim 1 we will quantify the effects of exposure to Aß ± HG or PA) on vascular function of leptomeningeal arterioles taken from AD, mild cognitive impairment (MCI) and cognitively normal (CN) subjects while identifying key inflammatory and oxidative stress signaling mechanisms modulating the responses. In Aim 2 we will establish the validity of peripheral adipose arterioles as a practical human surrogate model to study central brain arteriole response to AD stressors by comparing vascular, oxidative stress and inflammatory signaling responses in cadaver and living subject adipose arterioles exposed to Aß ± HG or PA to cadaver leptomeningeal arterioles. The proposal will provide novel mechanistic insights on the critical interaction and modulating effects
of cardiovascular risk factors and Aß on human micro vessels while comparing vascular responses to known AD stressors among AD, MCI and CN subjects. The validation of adipose arterioles as an acceptable surrogate to brain micro vessels will provide a practical human model to study mechanisms and treatments of early vascular injury from AD stressors.
描述(由申请人提供):血管疾病和心血管危险因素(糖尿病、高脂血症和高血压)与阿尔茨海默病(AD)密切相关,但它们导致 AD 的机制仍不清楚。目前人们已充分认识到血管功能障碍。导致脑灌注不足和血脑屏障功能受损发生在 AD 早期,并且在 AD 研究的早期病理生理学中发挥着核心作用,其中包括缺乏对心血管危险因素如何导致 AD 或调节的了解。 Aß 损伤,以及缺乏研究 AD 早期血管疾病的人体组织模型我们的初步数据表明,使用通过快速尸检从器官捐献者身上分离的离体软脑膜小动脉来研究对 Aß 和心血管危险因素的微血管反应的可行性。我们的总体目标是确定 Aß 诱导的微血管损伤的关键机制,并系统地研究心血管危险因素如何调节 Aß 对内皮功能、氧化应激和血管炎症的影响。 Aß 通过氧化应激和激活晚期糖基化终末产物受体 (RAGE) 和核因子 kappa B (NF-KB) 信号传导诱导内皮功能障碍和血管炎症,而高血糖 (HG) 和棕榈酸 (PA) 会加剧 Aß 血管毒性通过调节大脑和外周脂肪小动脉中的这些通路,在目标 1 中,我们将量化暴露于 Aß ± HG 或 PA) 对血管功能的影响。取自 AD、轻度认知障碍 (MCI) 和认知正常 (CN) 受试者的软脑膜小动脉,同时确定调节反应的关键炎症和氧化应激信号传导机制。在目标 2 中,我们将建立外周脂肪小动脉作为实用人类替代模型的有效性。通过比较尸体和活体受试者脂肪小动脉的血管、氧化应激和炎症信号反应,研究中枢脑小动脉对 AD 应激源的反应Aß ± HG 或 PA 与尸体软脑膜小动脉的关系 该提案将为关键相互作用和调节效应提供新的机制见解。
心血管危险因素和 Aß 对人体微血管的影响,同时比较 AD、MCI 和 CN 受试者对已知 AD 应激源的血管反应,验证脂肪小动脉作为脑微血管可接受的替代物,将为研究机制和治疗提供实用的人体模型。 AD 应激源造成的早期血管损伤。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Raymond Quezon Migrino其他文献
Raymond Quezon Migrino的其他文献
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