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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：
10394732
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/10394732
关键词：
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 Clinical Clonal Expansion Clustered Regularly Interspaced Short Palindromic Repeats Congestive Heart Failure Cytotoxic Chemotherapy DNA Sequence Alteration DNMT3a Data Development 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 Outcome PPM1D gene Patients Pharmaceutical Preparations Process Prognosis Property Protocols documentation Radiation Resistance Role Sampling Somatic Mutation Survivors TP53 gene Testing Time Toxic effect Treatment-Related Cancer age related base 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.

总结