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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：
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.

项目摘要随着最近抗癌治疗疗效的改善，癌症治疗相关的心脏毒性已经成为一个严重的临床问题。多柔比星诱导的心脏毒性（DIC）是最常见的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，纳米技术和工程化3D心脏微组织技术，我们将开发一个管道，使我们能够识别治疗目标和潜在的化学化合物，保护心肌细胞免于DIC。首先，我们将在阿霉素中进行全基因组扰动筛选利用CRISPR技术进行抗性检测。它将使我们能够识别出导致DIC的药物基因，对于DIC中的抵抗力至关重要。第二，我们将进行化学化合物的高通量筛选使用纳米粒子。它将使我们能够识别心脏保护化学物质，并编制一份心脏保护化学品。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，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，反映了复杂的细胞与细胞相互作用，微环境。该提案的目标是确定DIC的心脏保护治疗，这些平台可扩展到其他癌症治疗相关的心脏毒性。