Cardioprotective Therapy for Doxorubicin Using iPSC Microtissue and CRISPR Screening

项目总结 随着最近抗癌治疗疗效的提高，癌症治疗相关的心脏毒性 已经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 化疗相关的心脏毒性。在这里，将人类诱导多能干细胞(IPSCs)与 大规模CRISPR筛查、纳米技术和工程化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目标和潜在的化合物 保护心肌细胞免受DIC的影响。首先，我们将对阿霉素进行全基因组扰动筛选 使用CRISPR技术的电阻。这将使我们能够识别导致DIC或 对DIC中的耐药性是必不可少的。第二，我们将进行化合物的高通量筛选 使用纳米粒子。它将使我们能够识别保护心脏的化学物质，并编制一份保护心脏的 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，可以检测到 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，反映复杂的细胞-细胞相互作用和 微环境。这项建议目标是确定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。

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.