Translational pharmacoepidemiology: neuroprotection and neurotoxicity of antihypertensives and strong anticholinergics

转化药物流行病学：抗高血压药和强抗胆碱能药的神经保护和神经毒性

• 批准号: 10404980
• 负责人: SHELLY L GRAY
• 金额: $ 63.22万
• 依托单位: KAISER FOUNDATION RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-15 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10404980
• 关键词: Address; Adrenergic beta-Antagonists; Adult; Alzheimer' s Disease; Amyloid beta-Protein; Angiotensin II; Angiotensin Receptor; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Anti-Cholinergics; Antidepressive Agents; Antihistamines; Antihypertensive Agents; Benefits and Risks; Biological; Biological Assay; Blood; Blood Pressure; Brain; Cell Line; Cells; Chronic; Cohort Studies; Complement; Data; Dementia; Development; Drug usage; Engineering; Epidemiology; Exposure to; Human; In Vitro; Induced pluripotent stem cell derived neurons; Knowledge; Life course epidemiology; Link; Measurable; Measures; Medicine; Methodology; Methods; Modeling; Molecular; Nerve Degeneration; Neurons; Outcome; Participant; Pathologic; Pathway interactions; Pharmaceutical Preparations; Pharmacoepidemiology; Positioning Attribute; Regimen; Research; Resources; Risk; Science; Testing; Thiazide Diuretics; United States National Academy of Sciences; Ventricular; White Matter Hyperintensity; Work; base; brain health; brain volume; cohort; comparative; comparative effectiveness; computerized; dementia risk; drug testing; human stem cells; induced pluripotent stem cell; innovation; interest; middle age; neuroimaging; neuropathology; neuroprotection; neurotoxic; neurotoxicity; novel; population based; programs; receptor; standard measure; stem cell model; stem cells; translational approach; urologic

PROJECT 3 ABSTRACT Medications are an important exposure in the life course epidemiology framework that ties the Adult Changes in Thought (ACT) U19 Program together. Medications for chronic conditions are taken over several years, often beginning in mid-life, and chronic regimens achieve consistent blood levels, so toxic or protective brain effects of medication exposures are plausible. The Adult Changes in Thought (ACT) study has served as an incredible resource for cutting-edge dementia pharmacoepidemiology research for over 20 years. We take a multifaceted approach to examine links between common drugs and brain health by using an array of brain-related measures in the same cohort to deepen our understanding about these relationships and mechanisms. A considerable methodologic issue inherent in pharmocoepidemiology research is confounding by indication, where the condition for which a drug is prescribed is associated with dementia rather than the drug itself. In this Project, we take an innovative and translational approach to complement our existing pharmacoepidemology methods by deploying molecular assays that will directly address confounding by indication bias with a cell-based model using human induced pluripotent stem cell (hiPSC)-derived neurons (hiPSC-Ns) from ACT participants. The following Aims will be accomplished by working directly with all Project Cores. Aim 1: Deploy a human stem cell- based molecular assay to directly test mechanisms of neurotoxicity from anticholinergics (AChs) and address confounding by indication. We will deploy assays that measure four cellular outcomes: AD pathological molecules, Ab and pTau; neurotoxicity; and neuronal function. Aim 2: To determine comparative associations of antihypertensives (AHTs) with dementia and AD (2A), neuropathology (2B), and neuroimaging outcomes (2C), and test mechanisms of neuroprotection (2D). We will test the hypotheses that after controlling for their effects on blood pressure, exposure to Ang-II↑ drugs compared with Ang-II↓ drugs is associated with lower risk of dementia and AD, neuropathology and neuroimaging outcomes. We will test the hypothesis that Ang-II↑ drugs will have positive effects on cellular outcomes (i.e: Aβ and pTau, neurotoxicity and neuronal function) compared with an Ang-II↓ drug using the group of hiPSC-derived neurons developed in Aim 1. Our Project has important

项目 3 摘要 药物是生命历程流行病学框架中的一个重要暴露，它将成人的变化联系起来 一起思考 (ACT) U19 计划。治疗慢性病的药物通常要服用数年 从中年开始，长期治疗可达到稳定的血液水平，因此具有毒性或保护性大脑作用 的药物暴露是合理的。成人思想变化（ACT）研究是一项令人难以置信的研究 20 多年来前沿痴呆症药物流行病学研究的资源。我们采取多方面的 通过使用一系列与大脑相关的措施来检查常见药物与大脑健康之间的联系的方法 在同一队列中加深我们对这些关系和机制的理解。相当大的 药物流行病学研究固有的方法学问题因适应症而令人困惑，其中 开药治疗的病症与痴呆有关，而不是与药物本身有关。在这个项目中， 我们采用创新和转化方法来补充我们现有的药物流行病学方法 通过部署分子检测，直接解决基于细胞模型的指示偏差造成的混杂问题 使用来自 ACT 参与者的人类诱导多能干细胞 (hiPSC) 衍生的神经元 (hiPSC-Ns)。这 以下目标将通过直接与所有项目核心合作来实现。目标 1：部署人类干细胞 - 基于分子测定法直接测试抗胆碱能药物 (AChs) 的神经毒性机制并解决 通过指示混淆。我们将部署测量四种细胞结果的检测方法： AD 病理学 分子，Ab 和 pTau；神经毒性；和神经元功能。目标 2：确定以下内容的比较关联 抗高血压药 (AHT) 治疗痴呆和 AD (2A)、神经病理学 (2B) 和神经影像学结果 (2C)， 和测试神经保护机制（2D）。我们将测试这些假设，在控制其影响后 在血压方面，与 Ang-II↓ 药物相比，接触 Ang-II↑ 药物与较低的风险相关 痴呆和 AD、神经病理学和神经影像学结果。我们将检验 Ang-II↑ 药物的假设 相比之下，将对细胞结果（即：Aβ 和 pTau、神经毒性和神经元功能）产生积极影响 使用 Ang-II↓ 药物，使用目标 1 中开发的 hiPSC 衍生神经元组。 我们的项目有重要