# Modeling Tyrosine Kinase Inhibitor-Induced Vascular Dysfunction Using Human iPSCs

> **NIH NIH R01** · STANFORD UNIVERSITY · 2024 · $91,808

## Abstract

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.

## Key facts

- **NIH application ID:** 11002950
- **Project number:** 3R01HL141851-07S1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Wing H. WONG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $91,808
- **Award type:** 3
- **Project period:** 2018-08-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11002950

## Citation

> US National Institutes of Health, RePORTER application 11002950, Modeling Tyrosine Kinase Inhibitor-Induced Vascular Dysfunction Using Human iPSCs (3R01HL141851-07S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/11002950. Licensed CC0.

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