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Cardioprotective Therapy for Doxorubicin Using iPSC Microtissue and CRISPR Screening

使用 iPSC 微组织和 CRISPR 筛选对阿霉素进行心脏保护治疗

基本信息

批准号：
10296896
负责人：
JAYAKUMAR RAJADAS
金额：
$ 62.74万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-10 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10296896
关键词：
3-Dimensional Adherent Culture African American Anthracycline Asians Bar Codes Biocompatible Materials Bioinformatics Biomedical Engineering Breast Cancer Patient CRISPR screen CRISPR/Cas technology Cancer Etiology Cancer Patient Cancer Survivor Candidate Disease Gene Cardiac Cardiac Myocytes Cardiotoxicity Caucasians Cell Communication Cell Line Cells Chemicals Clinic Clinical Clinical Oncology Clustered Regularly Interspaced Short Palindromic Repeats Complex Data Development Developmental Biology Doxorubicin Drug Delivery Systems Drug Utilization Endothelial Cells Engineering Feedback Fibroblasts Gene Targeting Genes Genomics Goals Guide RNA Heart Heart failure Hispanics Human Immune checkpoint inhibitor Libraries Malignant Neoplasms Modeling Nanotechnology Oncology Patient-Focused Outcomes Patients Pharmaceutical Preparations Phenotype Predisposition Qi RNA library Radiation therapy Research Resistance Risk Assessment Risk Reduction Signal Transduction Technology Testing Treatment Efficacy Treatment-Related Cancer Tungsten Tyrosine Kinase Inhibitor anticancer treatment base cancer therapy candidate validation cardioprotection chemotherapy drug candidate drug repurposing drug use screening endonuclease ethnic diversity experience genome-wide high throughput screening improved induced pluripotent stem cell induced pluripotent stem cell technology nanoparticle prevent protective effect recruit screening side effect stem cell biology therapeutic candidate therapeutic target

项目摘要

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 identify cardioprotective therapy for DIC and to develop platforms that are expandable to other cancer treatment-related cardiotoxicities.

项目总结