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

摘要：项目3 空气污染，特别是可吸入颗粒物2.5微米(PM2.5)，渗入肺部通道，并进入 血液流动，造成呼吸、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引起损害的主要机制。 然而，对于所涉及的复杂的信号通路和机制，仍有许多知识空白 在细胞对PM2.5的反应中。更好地理解PM2.5诱导的分子和细胞基础 人类心肌细胞的结构和功能重塑将使我们能够开发新的医学方法 这可能会预防或减少与空气污染相关的心血管风险。此外，通过利用人类样本 不同的种族、民族和性别，这项研究将揭示遗传变异如何影响对 PM2.5，进一步方便了个性化用药。在这个项目中，我们将使用人类诱导的多能干细胞 (IPSCs)和3-D工程心脏组织(EHTS)，为疾病建模和 药物发现。因此，我们的具体目标是：目标1.建立研究大气污染的EHT模型-- 来自不同种族人群的相关心血管风险；目的2.阐明发病机制 用功能和组学分析研究PM2.5治疗后EHT的重塑机制； 对EHTS进行药物测试，并验证FDA批准的药物在预防空气污染相关方面的效果 心血管风险。

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.