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.

项目概要癌症治疗的心脏毒性可能导致癌症幸存者严重心力衰竭或停止治疗目前，在癌症治疗之前评估谁有发生心脏毒性的风险是一项挑战。癌症治疗和预防不良副作用的全基因组关联研究（GWAS）已取得进展。研究表明，遗传倾向是化疗风险易感性的关键决定因素之一一致地，患者对抗癌药物的敏感性。特异性诱导多能干细胞 (iPSC) 衍生的心肌细胞 (iPSC-CM)，反映供体该项目的目标是识别影响患者的基因和遗传变异。对抗癌药物的敏感性，用于开发心脏保护疗法和风险评估系统。尽管该提案的重点是阿霉素（阿霉素），它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，例如由首先，我计划确定可以抑制或激活的基因。使用我们基于 iPSC 的 CRISPR 筛选平台保护 iPSC-CM 免受阿霉素的影响。筛选的基因将。是阿霉素诱导的心脏毒性（DIC）的原因，因此是有希望的治疗靶标第二，我计划。利用生物工程技术和体内小鼠模型来评估候选疗法的效果比简单的单层培养系统更准确，因为批准药物的重新利用可以加速。为了研究结果的临床应用，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，为了开发一个系统来评估 DIC 的遗传易感性，我计划进行并行在 DIC 中使用基于 iPSC 的碱基/引物编辑筛选来表征许多遗传变异，并生成临床上与 DIC 相关的个体变异的“敏感性评分”结果将有助于降低风险。对接受化疗的患者进行分层。