Predicting and Preventing Chemotherapy-Induced Cardiotoxicity in African American Children
预测和预防非裔美国儿童化疗引起的心脏毒性
基本信息
- 批准号:10275329
- 负责人:
- 金额:$ 68.45万
- 依托单位:
- 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:2021-08-05 至 2026-07-31
- 项目状态:未结题
- 来源:
- 关键词:ATAC-seqAdolescentAdultAffectAfrican AmericanAgeAlgorithmsAmericanAnthracyclineAreaBiochemicalBiologicalBiological AssayBlastomaBody mass indexCRISPR/Cas technologyCancer PatientCandidate Disease GeneCardiac MyocytesCardiomyopathiesCardiotoxicityChestChildChromatinClinicalClinical DataClinical ResearchCommon Terminology Criteria for Adverse EventsComplicationCorrelation StudiesCoupledCryopreservationDataDetectionDoseDoxorubicinDrug PrescriptionsDrug usageEnhancersEtiologyEuropeanExposure toGene ExpressionGenesGeneticGenetic studyGenomeGenomicsGenotypeHeart TransplantationHeart failureHematologic NeoplasmsHigh PrevalenceHumanIn VitroIndividualKnowledgeLeadLinkage DisequilibriumMalignant Childhood NeoplasmMediatingMetabolismMethodologyModalityOncologistOnline SystemsParticipantPathway interactionsPatientsPerformancePharmaceutical PreparationsPhenotypePhysiologicalPredispositionProcessQuantitative Trait LociRARG geneRNA SplicingRadiation therapyRegulatory ElementResearchRiskRisk FactorsRoleRouteSaint Jude Children&aposs Research HospitalSamplingSingle Nucleotide PolymorphismSolidSurvivorsTimeTranslatingValidationVariantWorkalternative treatmentbasecancer diagnosiscardioprotectionchemotherapychildhood cancer survivorclinical applicationclinical riskcohortdifferential expressionepigenomeexperiencegenetic variantgenome editinggenome sequencinggenome wide association studygenomic toolshuman modelinduced pluripotent stem cellinnovationinterestleukemia/lymphomamembernovelpediatric patientspreventpromoterracial disparityresponserisk predictionrisk prediction modelsarcomasextooltranscriptometranscriptome sequencinguser-friendlywhole genome
项目摘要
Project Summary
Doxorubicin is a member of the anthracycline group of chemotherapy drugs prescribed to approximately 60% of
pediatric cancer patients suffering with sarcomas, blastomas, leukemia, and lymphoma. Although doxorubicin is
highly effective in these patients, ~16% of pediatric patients suffer doxorubicin-induced cardiotoxicity (DIC) which
can lead to heart failure requiring heart transplant. Our recent work has shown that DIC is 2.5x more
prevalent in African American (AA) survivors of childhood cancer. Despite more than 50 years of research
in this field, there is still, at present, little potential for either predicting or preventing DIC. There is an obvious
need for novel and innovative approaches to overcome this hurdle. Candidate gene and genome-wide
association studies, predominantly in Europeans, have identified >100 single nucleotide polymorphisms (SNPs)
that are statistically correlated with DIC, yet experimental validation has not been feasible due to the difficulty in
isolating and culturing human cardiomyocytes in vitro. In our recent work, we showed that patient-specific human
induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are efficient predictors of a patient’s
likelihood of developing DIC, confirming for the first time that there is a genomic basis to DIC. Here, we
hypothesize that hiPSC-CMs can be utilized in three different modalities to study genetic variants associated
with DIC in AA survivors: firstly, to discover novel predictive SNPs; secondly, to validate SNPs; and thirdly, to
examine the modulated pathways and determine genotype-specific cardioprotective methodologies. In Aim 1,
we will generate hiPSC from 100 AA adult survivors of childhood cancer with diverse biological covariates who
were exposed to doxorubicin assess their response to doxorubicin in vitro to validate our previous findings and
verify the power of this tool. In Aim 2, we will use these 100 patient-specific lines to identify drug response
differential expression, splicing and chromatin accessibility quantitative trait loci (deQTL, dsQTL and dcaQTL),
assessing biological covariates such as doxorubicin dose, age at cancer diagnosis, attained age, sex, BMI,
radiotherapy (other than involving chest), and cancer diagnosis both individually and combined. We will then
validate these variants with genome editing, and mechanistically examine pathways causative to DIC
susceptibility concentrating on genes with known roles in cardiomyopathy, cardioprotection, and doxorubicin
metabolism. We will then use the discoveries above to discover/repurpose genome-informed cardioprotective
drugs to prevent DIC in a genotype-specific manner. In Aim 3, we will build a risk prediction model for DIC among
AA survivors incorporating clinical risk factors and functionally assessed genetic variants above, evaluate its
prediction performance, validate it in independent AA survivors, and implement it in a web-based and user-
friendly tool for broader clinical and research use. In summary, this work will deliver us the genetic rationale for
why AA survivors experience DIC and provide 1, fully human validated SNP data for clinical application through
a user-friendly tool, and 2, novel cardioprotective pathways that can be targeted to protect against DIC.
项目摘要
多柔比星是蒽环类化疗药物的一员,约60%的
患有肉瘤、母细胞瘤、白血病和淋巴瘤的儿科癌症患者。虽然阿霉素是
在这些患者中非常有效,约16%的儿科患者患有阿霉素诱导的心脏毒性(DIC),
会导致心脏衰竭需要心脏移植我们最近的研究表明,DIC是2.5倍以上
在非洲裔美国人(AA)儿童癌症幸存者中普遍存在。尽管经过50多年的研究
在这一领域,目前预测或预防DIC的可能性仍然很小。有一个明显
需要新的和创新的方法来克服这一障碍。候选基因和全基因组
相关研究,主要是在欧洲人中,已经确定了>100个单核苷酸多态性(SNP)
与DIC在统计学上相关,但由于难以确定,实验验证尚不可行。
体外分离培养人心肌细胞。在我们最近的工作中,我们表明,
诱导的多能干细胞衍生的心肌细胞(hiPSC-CM)是患者的心肌损伤的有效预测因子。
发展DIC的可能性,首次证实DIC存在基因基础。这里我们
假设hiPSC-CM可以以三种不同的方式用于研究与hiPSC-CM相关的遗传变异,
与DIC在AA幸存者:首先,发现新的预测SNP;其次,验证SNP;第三,
检查调节的途径并确定基因型特异性心脏保护方法。在目标1中,
我们将从100名AA儿童癌症成年幸存者中产生hiPSC,这些幸存者具有不同的生物学协变量,
暴露于多柔比星,评估他们对多柔比星的体外反应,以验证我们先前的发现,
看看这个工具的威力。在目标2中,我们将使用这100条患者特异性线来确定药物反应
差异表达、剪接和染色质可及性数量性状基因座(deQTL、dsQTL和dcaQTL),
评估生物学协变量,例如阿霉素剂量、癌症诊断时的年龄、实际年龄、性别、BMI,
放射治疗(不涉及胸部)和癌症诊断(单独和组合)。然后我们将
通过基因组编辑验证这些变体,并机械地检查DIC的致病途径
易感性集中在已知在心肌病、心脏保护和阿霉素中起作用的基因上
新陈代谢.然后,我们将利用上述发现来发现/重新利用基因组信息的心脏保护作用。
以基因型特异性方式预防DIC的药物。在目标3中,我们将建立DIC的风险预测模型,
结合上述临床风险因素和功能评估的遗传变异的AA幸存者,评估其
预测性能,在独立的AA幸存者中验证它,并在一个基于网络和用户的
更广泛的临床和研究使用的友好工具。总之,这项工作将为我们提供遗传学的基本原理,
为什么AA幸存者会经历DIC,并通过以下方法提供1个完全人类验证的SNP数据用于临床应用:
一个用户友好的工具,和2,新的心脏保护途径,可以有针对性地防止DIC。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Paul W. Burridge其他文献
MorPhiC Consortium: towards functional characterization of all human genes
形态学联盟:致力于所有人类基因的功能表征
- DOI:
10.1038/s41586-024-08243-w - 发表时间:
2025-02-12 - 期刊:
- 影响因子:48.500
- 作者:
Mazhar Adli;Laralynne Przybyla;Tony Burdett;Paul W. Burridge;Pilar Cacheiro;Howard Y. Chang;Jesse M. Engreitz;Luke A. Gilbert;William J. Greenleaf;Li Hsu;Danwei Huangfu;Ling-Hong Hung;Anshul Kundaje;Sheng Li;Helen Parkinson;Xiaojie Qiu;Paul Robson;Stephan C. Schürer;Ali Shojaie;William C. Skarnes;Damian Smedley;Lorenz Studer;Wei Sun;Dušica Vidović;Thomas Vierbuchen;Brian S. White;Ka Yee Yeung;Feng Yue;Ting Zhou - 通讯作者:
Ting Zhou
Examining patient-specific responses to PARP inhibitors in a novel, human induced pluripotent stem cell-based model of breast cancer
在一种新颖的基于人类诱导多能干细胞的乳腺癌模型中检查患者对聚腺苷二磷酸核糖聚合酶抑制剂的特异性反应
- DOI:
10.1038/s41698-025-00837-5 - 发表时间:
2025-02-25 - 期刊:
- 影响因子:8.000
- 作者:
Carly J. Weddle;Malorie Blancard;Nnamdi Uche;Praeploy Pongpamorn;Romina B. Cejas;Paul W. Burridge - 通讯作者:
Paul W. Burridge
Serum Proteins Predict Treatment-Related Cardiomyopathy Among Survivors of Childhood Cancer
血清蛋白可预测儿童癌症幸存者中与治疗相关的心肌病
- DOI:
10.1016/j.jaccao.2024.10.004 - 发表时间:
2025-01-01 - 期刊:
- 影响因子:12.800
- 作者:
Suresh Poudel;Him Shrestha;Yue Pan;Qian Li;Kendrick Li;Cindy Im;Stephanie B. Dixon;Matthew J. Ehrhardt;Daniel A. Mulrooney;Suiping Zhou;Haiyan Tan;Anthony A. High;Paul W. Burridge;Smita Bhatia;John L. Jefferies;Kirsten K. Ness;Melissa M. Hudson;Leslie L. Robison;Gregory T. Armstrong;Junmin Peng;Yadav Sapkota - 通讯作者:
Yadav Sapkota
Paul W. Burridge的其他文献
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{{ truncateString('Paul W. Burridge', 18)}}的其他基金
Predicting and Preventing Chemotherapy-Induced Cardiotoxicity in African American Children
预测和预防非裔美国儿童化疗引起的心脏毒性
- 批准号:
10462680 - 财政年份:2021
- 资助金额:
$ 68.45万 - 项目类别:
Predicting and Preventing Chemotherapy-Induced Cardiotoxicity in African American Children
预测和预防非裔美国儿童化疗引起的心脏毒性
- 批准号:
10675503 - 财政年份:2021
- 资助金额:
$ 68.45万 - 项目类别:
HiDef B8: Commercialization and scaled production of defined, robust, and cost-effective media for iPSCs
HiDef B8:用于 iPSC 的明确、稳健且经济高效的介质的商业化和规模化生产
- 批准号:
10405556 - 财政年份:2021
- 资助金额:
$ 68.45万 - 项目类别:
HiDef B8: Commercialization and scaled production of defined, robust, and cost-effective media for iPSCs
HiDef B8:用于 iPSC 的明确、稳健且经济高效的介质的商业化和规模化生产
- 批准号:
10255392 - 财政年份:2021
- 资助金额:
$ 68.45万 - 项目类别:
Genomic Prediction of Doxorubicin-Induced Cardiotoxicity
阿霉素引起的心脏毒性的基因组预测
- 批准号:
10524092 - 财政年份:2018
- 资助金额:
$ 68.45万 - 项目类别:
Genomic Prediction of Doxorubicin-Induced Cardiotoxicity
阿霉素引起的心脏毒性的基因组预测
- 批准号:
10228683 - 财政年份:2018
- 资助金额:
$ 68.45万 - 项目类别:
Genomic Prediction of Doxorubicin-Induced Cardiotoxicity
阿霉素引起的心脏毒性的基因组预测
- 批准号:
10456312 - 财政年份:2018
- 资助金额:
$ 68.45万 - 项目类别:
Assessing the ability of hiCMs to recapitulate patient-specific doxorubicin-induced cardiotoxicity
评估 hiCM 重现患者特异性阿霉素引起的心脏毒性的能力
- 批准号:
10274149 - 财政年份:2018
- 资助金额:
$ 68.45万 - 项目类别:
Modeling the role of the genome in chemotherapy induced cardiotoxicity using iPSC
使用 iPSC 模拟基因组在化疗引起的心脏毒性中的作用
- 批准号:
9330916 - 财政年份:2015
- 资助金额:
$ 68.45万 - 项目类别:
Modeling the role of the genome in chemotherapy induced cardiotoxicity using iPSC
使用 iPSC 模拟基因组在化疗引起的心脏毒性中的作用
- 批准号:
9130233 - 财政年份:2015
- 资助金额:
$ 68.45万 - 项目类别:
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