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

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.