The role of the renin-angiotensin-endothelial pathway in AD

 描述(由申请人提供)：尽管我们对阿尔茨海默病(AD)病程的知识有所进步，但我们对这种毁灭性疾病的发病机制的了解仍然滞后。这项应用针对RFA-AG-15-010，旨在确定血管功能障碍在AD中的作用及其与内皮和血管紧张素途径相关的分子机制。我们建议评估先兆AD患者的全身和脑血管功能，确定它们的分子调节因子，并使用实验模型来确定这些通路和潜在的治疗干预措施的确切贡献。我们利用现有的队列(Emory心血管生物库和预测健康研究)；优秀的分子和翻译血管表型鉴定基础设施；我们机构正在进行的NIH资助的项目(Emory ADRC)；以及一支强大的跨学科团队，拥有心脏病学、血管生物学、认知衰老、神经科学、神经成像、代谢组学和生物信息学方面的专业知识。为了实现研究血管功能在AD中的作用的目标，我们将研究100名前驱AD患者(具有AD签名脑脊液(CSF)特征的MCI-AD)和100名匹配的认知正常个体2年，并使用一种新的AD大鼠模型(TgF344)，该模型也显示淀粉样蛋白和tau的变化2年。我们的目标是研究血管功能和再生能力在MCI-AD(AIM1)中的作用；利用探索性无偏代谢组学在MCI-AD(AIM2)中识别血管其他代谢途径中的脑脊液和血浆标志物(AIM2)；并使用大鼠AD动物模型建立血管功能障碍与AD轨迹之间的时间顺序，研究通过血管紧张素II阻断改变血管功能障碍对AD轨迹(AIM3)的影响。我们的初步工作表明：(1)全身和脑血管功能障碍导致认知损害；(2)血管功能的分子/细胞调节因子(氧化应激、肾素血管紧张素-醛固酮系统、血管内皮细胞活性和血管再生)与AD的认知功能和神经病理指标有关。我们打算在这项先前工作的基础上再接再厉，并将利用正在进行的研究，以确保招募拟议的样本(n=200)。我们在增强双向翻译能力的人类和大鼠研究中纳入了一组平行测量：对象位置认知范式、Aβ/tau水平，以及血管的可比测量。为了揭示潜在的已知和未知的分子调控因素，我们拥有尖端的代谢组学设施，并使用新颖的“代谢组学分析”方法对受试者的脑脊液和血浆进行分析。我们通过(I)通过基因表达和(Ii)在独立的脑脊液样本(N=800)中验证重要代谢物在AD中的作用。我们强大的血管表型计划基础设施和高度成功的跨学科团队使我们处于独特的位置，能够实现这项RFA的目标：识别新的血管生物标记物，并在AD早期提供新的血管靶向治疗。

 DESCRIPTION (provided by applicant): Despite advances in our knowledge of Alzheimer's disease (AD) course, our understanding of the pathogenesis of this devastating illness is lagging behind. This application, in response to RFA-AG-15-010, aims to identify the contribution of vascular dysfunction and its associated molecular mechanisms related to the endothelium and angiotensin pathways in AD. We propose to assess systemic and cerebral vascular functions and identify their molecular regulators in prodromal AD and use experimental models to define the precise contribution of these pathways and potential therapeutic interventions. We leverage existing cohorts (Emory Cardiovascular Biobank and Predictive Health Studies); excellent infrastructure for molecular and translational vascular phenotyping; ongoing NIH funded projects (Emory ADRC) at our institution; and a strong interdisciplinary team with expertise in cardiology, vascular biology, cognitive aging, neurosciences, neuroimaging, metabolomics and bioinformatics. To achieve this goal of studying the role of vascular function in AD, we will study 100 individuals with prodromal AD (MCI with AD-signature cerebrospinal fluid (CSF) profile, MCI-AD) and 100 matched cognitively normal individuals for 2 years and use a novel AD rat model (TgF344) that exhibits changes in both amyloid and tau also followed for 2 years. Our Aims are to investigate the role of vascular function and regenerative capacity in MCI-AD (AIM1); Identify CSF and plasma markers in vascular other metabolic pathways using explorative unbiased metabolomic profiling in MCI-AD (AIM2); and use a rat AD animal model to establish the chronological order between vascular dysfunction and AD trajectory and study the impact of modifying vascular dysfunction via angiotensin II blockade on AD trajectory (AIM3). Our preliminary work suggests that (i) systemic and cerebral vascular dysfunction contribute to cognitive impairments, and that (ii) molecular/cellular modulators of vascular function (oxidative stress (OS), renin angiotensin aldosterone system, endothelial activity and vascular regeneration) are related to cognitive function and neuropathological indicators of AD. We intend to build on this prior work and will leverage ongoing studies to ensure recruitment of the proposed sample (n=200). We incorporate a set of parallel measures in the human and rat studies enhancing 2-way translational capabilities: object location cognitive paradigm, Aβ/tau levels, and comparable measures of vascular. To uncover underlying known and unknown molecular regulators, we have a cutting edge metabolomic facility and use novel "metabolomic analysis of CSF and plasma of our participants. We validate the role of significant metabolite in AD in (i) our AD rats using gene expression and (ii) in an independent CSF sample (N=800). Our infrastructure of a strong vascular phenotyping program and a highly accomplished interdisciplinary team put us in a unique place to achieve the goals of this RFA: identify novel vascular biomarkers and provide new vascular-targeted therapies in early AD.