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<2.5µm的颗粒物（PM2.5），会渗透到肺通道并进入呼吸道。 血液，造成呼吸道，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引起损伤的主要机制。 然而，仍然有许多知识空白的复杂的信号通路和机制，涉及 对PM2.5的细胞反应。更好地了解PM2.5诱导的细胞和分子基础 人类心脏细胞的结构和功能重塑将使我们能够开发新的医疗方法， 可以预防或减少与空气污染相关的心血管风险。此外，通过使用人类样本， 不同的种族，种族和性别，这项研究将揭示遗传变异如何影响毒性反应， PM2.5，进一步促进个性化医疗。在这个项目中，我们将使用人类诱导多能干细胞 （iPSCs）和3-D工程心脏组织（EHT），为疾病建模和 药物发现。因此，我们的具体目标是：目标1。建立用于研究空气污染的EHT模型- 相关的心血管风险从一个种族多样化的群体的个人;目的2。阐明病理 EHT对PM2.5处理的反应性重塑机制，功能和组学分析;和目的3. 对EHT进行药物测试，并验证FDA批准的药物在预防与空气污染有关的 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.