R01HL150693

Cardioprotective Therapy for Doxorubicin Using iPSC Microtissue and CRISPR Screening - Project Summary

In tandem with recent improvements in anti-cancer treatment efficacy, cancer treatment-related cardiotoxicity has become a serious clinical problem. Doxorubicin-induced cardiotoxicity (DIC) is one of the most common chemotherapy-related cardiotoxicities.

Here, combining human induced pluripotent stem cells (iPSCs) with large-scale CRISPR screening, nanotechnology, and engineered 3D cardiac microtissue technology, we will develop a pipeline which enables us to identify therapeutic targets and potential chemical compounds that protect cardiomyocytes from DIC.

First, we will perform genome-wide perturbation screening in doxorubicin resistance using CRISPR technology. It will enable us to identify druggable genes that are causative for DIC or essential for resistance in DIC.

Second, we will perform high-throughput screening of chemical compounds using nanoparticles. It will enable us to identify cardioprotective chemicals and compile a cardioprotective drug repurposing library.

Third, we will develop a 3D cardiac microtissue platform that can detect cardioprotective effects of the candidate therapies. The 3D cardiac microtissue will consist of iPSC-derived cardiomyocytes, endothelial cells, and fibroblasts, reflective of complex cell-cell interaction and microenvironment.

The goal of this proposal is to identify cardioprotective therapy for DIC and to develop platforms that are expandable to other cancer treatment-related cardiotoxicities.

The Leland Stanford Junior University

TO FOSTER HEART AND VASCULAR RESEARCH IN THE BASIC, TRANSLATIONAL, CLINICAL AND POPULATION SCIENCES, AND TO FOSTER TRAINING TO BUILD TALENTED YOUNG INVESTIGATORS IN THESE AREAS, FUNDED THROUGH COMPETITIVE RESEARCH TRAINING GRANTS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Stanford, California 94305 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the End Date has been extended from 07/31/25 to 08/31/30 and the total obligations have increased 433% from $627,358 to $3,345,164.