Modeling Cardiovascular Risks of Air Pollutants with Human Induced Pluripotent Stem Cell-Derived Cardiovascular-Associated Cells (Project 3) for the Air pollution disrupts Inflammasome Regulation in

使用人类诱导多能干细胞衍生的心血管相关细胞（项目 3）模拟空气污染物的心血管风险，以了解空气污染扰乱炎症体调节的情况

• 批准号: 10269336
• 负责人: Joseph C. Wu
• 金额: $ 62.03万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10269336
• 关键词: 3-Dimensional; Acute; Affect; Air Pollutants; Air Pollution; Anti-Inflammatory Agents; Antiinflammatory Effect; Area; Arrhythmia; Asthma; Biological Assay; Blood Circulation; Calcium; Caliber; Cardiac; Cardiac Myocytes; Cardiopulmonary; Cardiotoxicity; Cardiovascular Models; Cardiovascular system; Cell Survival; Cells; Chronic; Cytokine Signaling; Development; Disease model; Drug Compounding; Endothelial Cells; Environmental Health; Ethnic Origin; Exposure to; FDA approved; Fibroblasts; Gender; Gene Expression; Genetic Variation; Health; Heart; Heart Diseases; Human; Immune signaling; Immune system; Individual; Inflammasome; Inflammation; Inflammatory; Interleukin-1; Interleukin-1 beta; Knowledge; Lung; Medical; Mitochondria; Modeling; Molecular; Morbidity - disease rate; Morphology; Myocardial Ischemia; Organ; Oxidative Stress; Particulate Matter; Pathologic; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Physiological; Pollution; Prevention; Race; Regulation; Risk; Sampling; Serum; Signal Pathway; Stroke; Structure; Study models; Sudden Death; Testing; Tissue Engineering; Tissue Model; Tissues; Toxic effect; Wildfire; World Health Organization; base; biobank; cardiac tissue engineering; cardiovascular risk factor; cell type; cerebrovascular; cohort; cytokine; drug discovery; drug testing; genotoxicity; high throughput screening; improved; induced pluripotent stem cell; innovation; lung injury; mortality; novel; personalized medicine; pollutant; prevent; racial diversity; recruit; respiratory; response; transcriptome

ABSTRACT: PROJECT 3 Air pollution, particularly particulate matter <2.5µm (PM2.5), penetrates into lung passageways and enters the bloodstream, causing respiratory, cardiovascular, and cerebrovascular damage. Recent studies suggest that oxidative stress, genotoxicity, and inflammation to be the central mechanisms by which PM2.5 induced damage. However, there are still many knowledge gaps of the intricate signal pathways and mechanisms that are involved in the cellular responses to PM2.5. A better understanding of the molecular and cellular basis of the PM2.5-induced structural and functional remodeling in human cardiac cells will allow us to develop novel medical approaches that could prevent or reduce air pollution-related cardiovascular risks. Moreover, by utilizing human samples of different race, ethnicity, and gender, this study will reveal how genetic variations affect the toxicity response to PM2.5, further facilitating personalized medicine. In this project, we will use human induced pluripotent stem cells (iPSCs) and 3-D engineered heart tissues (EHTs) that provide innovative opportunities for disease modeling and drug discovery. Therefore, our specific aims are to: Aim 1. establish EHT models for the study of air pollution- related cardiovascular risks from a racially diverse group of individuals; Aim 2. elucidate the pathological remodelling mechanisms of EHT in response to PM2.5 treatment with functional and omics analysis; and Aim 3. perform drug testing on EHTs and validate the effects of FDA approved drugs in prevention of air pollution-related cardiovascular risks.

摘要：项目3 空气污染，特别是特定物质<2.5µm（PM2.5），渗透到肺通道中并进入 血液会导致呼吸道，心血管和脑血管损伤。最近的研究表明 氧化应激，遗传毒性和炎症是PM2.5诱导损伤的中心机制。 但是，涉及的复杂信号途径和机制仍然存在许多知识差距 在细胞对PM2.5的反应中。更好地了解PM2.5诱导的分子和细胞基础 人类心脏细胞中的结构和功能重塑将使我们能够开发新的医学方法 这可以防止或减少与空气污染相关的心血管风险。而且，通过使用人类样本 不同种族，种族和性别，这项研究将揭示遗传变异如何影响对 PM2.5，进一步支持个性化医学。在这个项目中，我们将使用人类诱导的多能干细胞 （IPSC）和3-D工程心脏组织（EHT），为疾病建模和 药物发现。因此，我们的具体目的是：目标1。建立EHT模型以研究空气污染 - 来自大致多样化的个体的相关心血管风险；目标2。阐明病理 EHT的重塑机制响应PM2.5处理功能和OMICS分析；和目标3。 对EHT进行药物测试，并验证FDA批准的药物预防与空气污染有关的影响 心血管风险。