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

肾素-血管紧张素-内皮途径在 AD 中的作用

• 批准号: 9482119
• 负责人: IHAB M HAJJAR
• 金额: $ 29.8万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9482119
• 关键词: Adult; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloid beta-Protein; Amyloidosis; Angiotensin II; Angiotensin Receptor; Angiotensins; Animal Disease Models; Animals; Awareness; Bioinformatics; Biological Markers; Biology; Biology of Aging; Blood Vessels; Brain; Cardiology; Cardiovascular Diseases; Cardiovascular system; Cerebrospinal Fluid; Cerebrovascular Circulation; Cerebrovascular Disorders; Chronology; Clinical; Cognitive; Cognitive aging; Cognitive deficits; Dementia; Disease; Disease Progression; Endothelium; Ensure; Exhibits; Experimental Models; Funding; Future; Gene Expression; Goals; Health; Human; Impaired cognition; Individual; Institution; Knowledge; Life; Location; Longitudinal Studies; Measures; Metabolic Pathway; Modeling; Molecular; Natural regeneration; Nerve Degeneration; Neurosciences; Oxidative Stress; Participant; Pathogenesis; Pathway interactions; Phenotype; Plasma; Positioning Attribute; Rattus; Recruitment Activity; Renin; Renin-Angiotensin-Aldosterone System; Research; Research Infrastructure; Risk; Risk Factors; Role; Sampling; Tauopathies; Therapeutic Intervention; Translating; Translations; United States National Institutes of Health; Vascular Diseases; Work; biobank; cerebrovascular; cognitive function; cohort; differential expression; endothelial dysfunction; hippocampal atrophy; hypoperfusion; metabolomics; mild cognitive impairment; neuroimaging; neuron loss; neuropathology; novel; programs; public health relevance; regenerative; response; targeted treatment; tau Proteins; therapeutic target; vascular contributions

 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.

 描述（由申请人提供）：尽管我们对阿尔茨海默病（AD）过程的了解有所进展，但我们对这种毁灭性疾病的发病机制的理解仍然落后。作为对RFA-AG-15-010的响应，本申请旨在确定血管功能障碍的贡献及其与AD中内皮和血管紧张素通路相关的相关分子机制。我们建议评估全身和脑血管功能，并确定其分子调节剂前驱AD和使用实验模型，以确定这些途径和潜在的治疗干预的精确贡献。我们利用现有的队列（Emory Cardiovascular Biobank和Predictive Health Studies）;分子和翻译血管表型的优秀基础设施;我们机构正在进行的NIH资助项目（Emory ADRC）;以及强大的跨学科团队，具有心脏病学，血管生物学，认知老化，神经科学，神经影像学，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中的作用这一目标，我们将研究100名前驱AD患者（具有AD特征脑脊液（CSF）特征的MCI，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（TgF 344），该模型显示淀粉样蛋白和tau蛋白的变化也随访2年。我们的目的是研究血管功能和再生能力在MCI-AD（AIM 1）中的作用;使用探索性无偏代谢组学分析确定MCI-AD（AIM 2）中血管其他代谢途径的CSF和血浆标志物;并利用大鼠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阻断来改善血管功能障碍对AD的影响弹道（AIM 3）。我们的初步工作表明，（i）全身和脑血管功能障碍导致认知障碍，（ii）血管功能的分子/细胞调节剂（氧化应激（OS），肾素血管紧张素醛固酮系统，内皮活性和血管再生）与认知功能和AD的神经病理学指标有关。我们打算在此之前的工作的基础上，并将利用正在进行的研究，以确保招募拟议的样本（n=200）。我们在人类和大鼠研究中纳入了一组平行措施，以增强双向翻译能力：物体定位认知范式，Aβ/tau水平和血管的可比措施。为了揭示潜在的已知和未知的分子调节因子，我们拥有先进的代谢组学设备，并对参与者的CSF和血浆进行了新的代谢组学分析。我们在（i）使用基因表达的AD大鼠和（ii）独立CSF样品（N=800）中验证了AD中重要代谢物的作用。我们强大的血管表型分析计划和高度成就的跨学科团队的基础设施使我们处于一个独特的位置，以实现该RFA的目标：识别新的血管生物标志物，并在早期AD中提供新的血管靶向治疗。

项目成果

Trends in prevalence of comorbidities in heart failure clinical trials.

• DOI: 10.1002/ejhf.1818
• 发表时间: 2020-06
• 期刊: European journal of heart failure
• 影响因子: 18.2
• 作者: Khan MS;Samman Tahhan A;Vaduganathan M;Greene SJ;Alrohaibani A;Anker SD;Vardeny O;Fonarow GC;Butler J
• 通讯作者: Butler J

Development of digital voice biomarkers and associations with cognition, cerebrospinal biomarkers, and neural representation in early Alzheimer's disease.

• DOI: 10.1002/dad2.12393
• 发表时间: 2023-01
• 期刊: Alzheimer's & dementia (Amsterdam, Netherlands)

Do Women and Men Respond Similarly to Therapies in Contemporary Heart Failure Clinical Trials?

在当代心力衰竭临床试验中，女性和男性对治疗的反应是否相似？

• DOI: 10.1016/j.jchf.2018.12.016
• 发表时间: 2019
• 期刊: JACC. Heart failure
• 作者: Vaduganathan,Muthiah;Tahhan,AymanSamman;Alrohaibani,Alaaeddin;Greene,StephenJ;Fonarow,GreggC;Vardeny,Orly;Lindenfeld,JoAnn;Jessup,Mariell;Fiuzat,Mona;O'Connor,ChristopherM;Butler,Javed
• 通讯作者: Butler,Javed