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Role of therapy-related clonal hematopoiesis in anthracycline-induced cardiotoxicity

治疗相关克隆造血在蒽环类药物引起的心脏毒性中的作用

基本信息

批准号：
10614493
负责人：
KENNETH WALSH
金额：
$ 40.38万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10614493
关键词：
Acceleration Address Age Aging Animal Model Anthracycline Antineoplastic Agents Biological Assay Biological Models Blood Blood Cells Cancer Patient Cancer Survivor Cardiology Cardiomyopathies Cardiotoxicity Cardiovascular Diseases Cardiovascular system Caring Cell Culture Techniques Cell physiology Cells Cessation of life Chemotherapy and/or radiation Clinical Clonal Expansion Clustered Regularly Interspaced Short Palindromic Repeats Congestive Heart Failure Cytotoxic Chemotherapy DNA Sequence Alteration DNMT3a Data Development Disease Doxorubicin Elderly Epigenetic Process Event Exhibits Exposure to Frequencies Gene Mutation Genes Genotoxic Stress Heart Heart Diseases Heart failure Hematopoiesis Hematopoietic Hematopoietic System Hematopoietic stem cells Human Immune Individual Inflammation Inflammatory Link Malignant Neoplasms Mediating Modeling Molecular Mosaicism Mus Mutate Mutation Myeloid Cells Myocardial dysfunction Neutrophil Activation Outcome PPM1D gene Patients Pharmaceutical Preparations Probability Process Prognosis Property Protocols documentation Resistance Role Sampling Somatic Mutation Survivors TP53 gene Testing Time Toxic effect Treatment-Related Cancer age related cancer therapy cardioprotection cardiovascular disorder risk chemokine chemotherapy clinically relevant conditional mutant cytokine exome sequencing experimental study fitness in vivo insight irradiation mouse genetics mouse model mutant neutrophil novel novel therapeutics overexpression preclinical study prevent targeted treatment therapy design

项目摘要

SUMMARY The accumulation of somatic DNA mutations in driver genes within the hematopoietic system can provide a fitness advantage to the mutant cell and thus allow for its clonal expansion. This process is referred to as clonal hematopoiesis and leads to a situation where a substantial fraction of an individual’s blood cells are replaced by clones with the driver gene mutation. Previous large exome sequencing studies in humans have shown that these somatic mutations accumulate during aging and are associated with a higher rate of cardiovascular-related deaths. Moreover, recent experimental studies support the idea that clonal hematopoiesis causally promotes cardiovascular disease (CVD). More recently, genotoxic stresses such as radiation or chemotherapy have also been shown to facilitate hematopoietic clonal expansion in cancer patients. Compared with age-related clonal hematopoiesis that is mediated primarily by mutations in epigenetic regulators such as DNMT3A and TET2, clonal hematopoiesis resulting from prior exposure to cytotoxic therapy is uniquely associated with high frequencies of mutations in TP53 and PPM1D. This clonal selection/expansion of TP53 and PPM1D mutant clones by cancer therapy may subsequently increase the risk of CVD, and addressing this clinically-relevant question represents the main objective of the current proposal. In fact, over the past decade, the number of cancer survivors has grown, thus there has been a paradigm shift in the approach to survivor care with a renewed focus on maximizing non-cancer-related outcomes, such as CVD. Therefore, there is an unmet need to understand the potential connection between cancer-therapy related clonal hematopoiesis and CVD. Thus, this study aims to examine whether a causal connection exists between therapy-related clonal hematopoiesis and chemotherapy-associated cardiomyopathy. As a proof-of-concept, I will test the hypothesis that TP53- and PPM1D-mediated clonal hematopoiesis contributes to anthracycline-induced cardiomyopathy using sophisticated animal models.

摘要在造血系统内驱动基因中体细胞DNA突变的积累可以提供一种对突变细胞的适应性优势，从而允许其克隆性扩张。这个过程被称为克隆并导致一种情况，即一个人的血细胞的很大一部分被克隆司机基因突变。此前对人类的大型外显子组测序研究表明，这些体细胞突变在衰老过程中积累，并与心血管相关疾病的较高发生率有关死亡。此外，最近的实验研究支持这样一种观点，即克隆性造血可以因果地促进心血管疾病(CVD)。最近，基因毒性压力，如放射或化疗，也已被证明能促进癌症患者的造血细胞克隆性扩张。与年龄相关的克隆相比主要由DNMT3A和TET2等表观遗传调节因子突变介导的造血，先前接受细胞毒治疗导致的克隆性造血与高 TP53和PPM1D基因突变频率。TP53和PPM1D突变体的克隆筛选/扩增通过癌症治疗进行克隆可能随后增加心血管疾病的风险，并解决这一临床相关问题这一问题代表了当前提案的主要目标。事实上, 在过去的十年里，癌症幸存者的人数有所增加，因此幸存者护理方法发生了范式转变，出现了新的专注于最大化非癌症相关的结果，如心血管疾病。因此，有一种未得到满足的需求了解癌症治疗相关的克隆性造血和心血管疾病之间的潜在联系。因此，这一点这项研究旨在检查与治疗相关的克隆性造血和化疗相关的心肌病。作为概念验证，我将测试TP53-和 PPM1D介导的克隆性造血在蒽环类药物诱导的心肌病中的作用复杂的动物模型。