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Parallel Characterization of Genetic Variants in Chemotherapy-Induced Cardiotoxicity Using iPSCs

使用 iPSC 并行表征化疗引起的心脏毒性中的遗传变异

基本信息

批准号：
10663613
负责人：
Masataka Nishiga
金额：
$ 13.21万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10663613
关键词：
3-Dimensional Acceleration Address Adherent Culture Affect Age Anthracycline Antineoplastic Agents Biological Biomedical Engineering Blood Pressure CRISPR screen CRISPR/Cas technology Cancer Patient Cancer Survivor Candidate Disease Gene Cardiac Cardiotoxicity Cardiovascular system Cells Characteristics Chemicals ClinVar Clinical Clinical Research Clustered Regularly Interspaced Short Palindromic Repeats DNA Damage Data Set Dose Doxorubicin Drug Targeting Drug usage Echocardiography Electrophysiology (science)Endothelial Cells Engineering Etiology Evaluation Extracellular Matrix Feedback Fibroblasts Gender Gene Expression Genes Genetic Predisposition to Disease Genomics Goals HTATIP gene Heart Heart failure Histology Human Immunology Impairment Individual International Malignant Childhood Neoplasm Malignant Neoplasms Mechanics Mentors Mitochondria Modeling Multiomic Data Mus Myocardium Oncology Oxidative Stress Pathway interactions Patients Pharmaceutical Preparations Phase Phenotype Phosphotransferases Predisposition Production Qi Radiation therapy Research Risk Risk Assessment Risk Factors Signal Transduction Stretching Supervision System Technology Testing Tissue Engineering Tissue Model Tissues Training Tyrosine Kinase Inhibitor UGT1A1 gene Validation Variant angiogenesis base base editor cancer survival cancer therapy cardioprotection career development cell type chemotherapy clinical application experimental study genetic information genetic makeup genetic variant genome wide association study genome wide screen genome-wide heart damage heart metabolism improved in vivo induced pluripotent stem cell induced pluripotent stem cell derived cardiomyocytes induced pluripotent stem cell technology inhibitor therapy leukemia malignant breast neoplasm mouse model paracrine patient stratification prevent prime editing prime editor programs protective effect risk stratification scale up screening side effect single-cell RNA sequencing skills therapeutic target

项目摘要

Project Summary Cardiotoxicity of cancer treatments can lead to severe heart failure in cancer survivors or discontinuation of cancer treatments. Currently, it is challenging to evaluate who is at the risk of developing cardiotoxicity prior to cancer treatments and prevent the adverse side effects. Genome-wide association studies (GWASs) have shown that genetic predispositions are one of the key determinants of risk susceptibility to chemotherapy- induced cardiotoxicity. Consistently, the susceptibility to anti-cancer agents can be recapitulated by patient- specific induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iPSC-CMs), which reflect the donor patients’ genetic makeup. The goal of this project is to identify genes and genetic variants that affect the susceptibility to anti-cancer agents for developing cardio-protective therapies and risk assessment systems. Although this proposal focuses on doxorubicin, which is one of the most commonly-used anti-cancer agents, the approach described here is expandable to any other cancer treatment-induced cardiotoxicities such as those by tyrosine kinase inhibitors and radiation therapy. First, I plan to identify genes whose inhibition or activation can protect iPSC-CMs from doxorubicin using our iPSC-based CRISPR screening platform. The screened genes will be causative in doxorubicin-induced cardiotoxicity (DIC) and thus promising therapeutic targets. Second, I plan to utilize bioengineering technologies and in vivo mouse models to assess the effects of candidate therapies more accurately than simple monolayer culture systems. Since repurposing of approved drugs can accelerate the clinical application of the findings, I plan to test existing drugs that target the validated genes in these models. Finally, to develop a system to evaluate the genetic susceptibility to DIC, I plan to perform parallel characterization of many genetic variants using iPSC-based base/prime-editing screens in DIC and generate “susceptibility scores” of individual variants that are clinically implicated in DIC. The result will help with risk stratification of patients who receive chemotherapies.

项目摘要癌症治疗的心脏毒性可导致癌症幸存者的严重心力衰竭或停止癌症治疗。目前，评估谁有发生心脏毒性的风险是具有挑战性的治疗癌症，防止不良副作用。全基因组关联研究(GWAS) 研究表明，遗传倾向是化疗风险易感性的关键决定因素之一诱发心脏毒性。一如既往，抗癌药物的敏感性可以由患者概括- 特异性诱导多能干细胞(IPSC)来源的心肌细胞(IPSC-CMS)，反映供体病人的基因构成。这个项目的目标是确定影响基因和遗传变异的基因和变异开发心脏保护疗法和风险评估系统时对抗癌药物的敏感性。虽然这项提案的重点是阿霉素，这是最常用的抗癌药物之一，但这里描述的方法可以扩展到任何其他癌症治疗引起的心脏毒性，例如通过酪氨酸激酶抑制剂和放射治疗。首先，我计划识别其抑制或激活可以使用我们基于IPSC的CRISPR筛查平台保护IPSC-CMS免受阿霉素的伤害。筛选出的基因将是阿霉素引起的心脏毒性(DIC)的病因，因此有希望成为治疗的靶点。第二，我计划利用生物工程技术和活体小鼠模型评估候选疗法的效果比简单的单层培养系统更准确。因为重新调整已批准药物的用途可以加快为了将这一发现应用于临床，我计划测试针对这些模型中经过验证的基因的现有药物。最后，为了开发一个评估DIC遗传易感性的系统，我计划并行执行在DIC和GENERATE中使用基于IPSC的碱基/质数编辑屏幕对多种遗传变异进行表征临床上与DIC有牵连的个体变异的“敏感性分数”。这一结果将有助于降低风险对接受化疗的患者进行分层。