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 药物是生命课程流行病学框架的重要接触 思想（ACT）U19程序一起。慢性疾病的药物经常服用几年 从中期开始，慢性方案达到一致的血液水平，因此有毒或受保护的大脑影响 药物暴露是合理的。成人思想变化（ACT）研究是令人难以置信的 尖端痴呆痴呆症药物学研究的资源已有20多年了。我们采取了一个多方面的 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联系的方法 在同一队列中，我们加深了我们对这些关系和机制的理解。一个很大的 药学上的方法论问题研究中固有的方法论问题是通过指示混淆的， 规定药物的条件与痴呆症相关，而不是药物本身。在这个项目中， 我们采用一种创新和翻译的方法来完成我们现有的药物ePIDEMOLOGY方法 通过部署分子测定，该测定将直接解决与基于细胞模型的指示偏差的混杂 使用人类诱导的多能干细胞（HIPSC）衍生的神经元（HIPSC-NS）来自ACT参与者。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 - 基于分子测定直接测试抗胆碱能药物（ACHS）和地址的神经毒性机制 通过指示混淆。我们将部署测量四个细胞结果的测定法：AD病理 分子，AB和PTAU；神经毒性；和神经元功能。目标2：确定比较关联 具有痴呆和AD（2A），神经病理学（2B）和神经影像学结果（2C），2C）的抗高血压（AHTS）， 和神经保护的测试机制（2D）。我们将测试在控制其效果之后的假设 在血压下，与Ang-II↓药物相比，ANG-II↑药物的暴露与较低的风险有关 痴呆和AD，神经病理学和神经影像学结果。我们将测试ANG-II↑药物的假设 将对细胞结局（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AIM 1中的HIPSC衍生神经元组。 我们的项目很重要