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：
10463762
负责人：
JAYAKUMAR RAJADAS
金额：
$ 76.88万
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/10463762
关键词：
3-Dimensional Adherent Culture African American Anthracycline Asian 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 Hispanic Human Immune checkpoint inhibitor Libraries Malignant Neoplasms Modeling Nanotechnology Oncology Patient-Focused Outcomes Patients Persons 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 checkpoint therapy 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 derived cardiomyocytes induced pluripotent stem cell technology inhibitor therapy 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.

项目概要随着最近抗癌治疗功效的提高，癌症治疗相关的心脏毒性已成为一个严重的临床问题。阿霉素引起的心脏毒性（DIC）是最常见的心脏毒性之一化疗相关的心脏毒性。在这里，将人类诱导多能干细胞 (iPSC) 与大规模 CRISPR 筛选、纳米技术和工程 3D 心脏微组织技术，我们将开发一条管道，使我们能够识别治疗靶点和潜在的化合物保护心肌细胞免受 DIC 侵害。首先，我们将对阿霉素进行全基因组扰动筛选使用 CRISPR 技术产生抗性。它将使我们能够识别导致 DIC 或 DIC 的可药物基因对于 DIC 的耐药性至关重要。其次，我们将进行化合物的高通量筛选使用纳米颗粒。它将使我们能够识别心脏保护化学物质并编制心脏保护剂药物再利用图书馆。第三，我们将开发一个3D心脏微组织平台，可以检测候选疗法的心脏保护作用。 3D 心脏微组织将由 iPSC 衍生的心肌细胞、内皮细胞和成纤维细胞，反映了复杂的细胞间相互作用和微环境。该提案的目标是确定 DIC 的心脏保护疗法并开发可扩展到其他癌症治疗相关心脏毒性的平台。