PROJECT SUMMARY Tyrosine kinase inhibitors (TKIs) have been shown to significantly decrease a variety of malignancy-related mortality in the past two decades. However, concerns have been raised due to their potential vascular toxicity that could lead to hypertension, myocardial infarction, stroke, and peripheral arterial diseases. Despite these safety concerns, the mechanisms underlying TKI-induced vascular toxicity (TKI-VT) are poorly understood. To overcome this challenge, we propose to leverage human iPSCs, state-of-the-art multi-omics methods, and CRISPR screening to investigate molecular and cellular mechanisms of TKI-VT and identify druggable targets that can be further tested in animal models. Specifically, in Aim 1, we will comprehensively profile in vitro phenotypes of TKI-VT using iPSC-derived cardiac pericytes (PCs), an important but rarely explored cardiac cell type, in a 2D monolayer to define cellular mechanisms of TKI-VT. In Aim 2, we will evaluate how TKIs induce disrupted cellular crosstalk between iPSC-PCs and iPSC-endothelial cells (iPSC-ECs) by performing integrative omics on a vessel-on-chip model. We anticipate that the successful completion of these studies will lead to novel mechanistic insights into TKI-VT pathogenesis and help develop promising therapeutic strategies that can prevent and/or treat TKI-VT on cancer patients who require chronic TKI treatment or whose life expectancy can be restored to normal after short-term treatment. Moreover, this proposal will help define the role of TKIs in vascular pathophysiology, which may have broad scientific and clinical implications beyond cardio-oncology. Proposed Supplement: In the last decade alone, the Hispanic population in the United States has grown by 23% to 62.1 million individuals, making it the fastest-growing minority ethnic group. Cardiovascular diseases (CVDs) present a significant health risk to Hispanics, with a higher risk than all other ethnic groups. This community faces unique risk factors for CVDs, the nuances of which remain elusive largely due to underrepresentation in clinical trials and gaps in understanding their specific cardiac health differences. To address this, this diversity supplement will extend the scope of the parent R01 to further understand TKI-VT in Hispanic populations. In Aim 1, this proposal will derive iPSC-ECs and iPSC-PCs from Hispanics and introduce TKIs to evaluate changes in cellular functions, oxidative stress, and cell fate plasticity in monolayers. In Aim 2, the same iPSC-ECs and iPSC-PCs will be used to construct 3D Vessel-on-Chip models to identify TKI-induced changes in vascular cell crosstalk that may trigger vascular dysfunction. This supplement is an important opportunity to extend the understanding of cardiovascular health differences in the Hispanic population.