Juvenile mouse model of delayed anthracycline cardiotoxicity

描述（由申请人提供）：虽然蒽环类药物如多柔比星（DOX）是最有效的化疗药物之一，通常用于治疗儿科癌症，但它们存在问题，因为它们与心脏毒性有关。儿童癌症的总体存活率为70- 90%，暴露于蒽环类药物的年轻人数量正在稳步上升。在成人中，这将累积剂量限制为550 mg/m2，但在儿童中，最大累积剂量不得超过300 mg/m2。即使治疗不超过这个限度，心力衰竭也可能在最初暴露后数年发展。儿童比成人更容易受到蒽环类药物诱导的心肌损害，并且蒽环类药物暴露时儿童年龄越小，心力衰竭的风险越高。不幸的是，心力衰竭可能在最初暴露于蒽环类药物后数年表现出来，此时对心脏的需求增加，例如在怀孕或运动期间。为了了解这个问题，我们建立了一个小儿蒽环类药物心脏毒性的小鼠模型，并在此建议中，我们将研究迟发性心脏毒性的机制。我们假设蒽环类药物对心肌细胞造成持久的损伤，导致收缩机制或线粒体功能受损。蒽环类药物通过对肿瘤血管生成的负面影响发挥其抗肿瘤作用;这也是化疗期间脱发的基础，因为支持毛囊的血管结构渐开线。儿童区别于成人的一个关键特征是心脏仍在生长，必须有匹配的血管生成来支持心肌。我们假设蒽环类药物损害发育中心脏的血管生成，从而限制了对增加的需求的反应能力，特别是随着心脏的生长。鉴于最近的工作表明心脏驻留干细胞的可能性，我们认为儿童时期的心脏生长和怀孕期间可能的生理性“肥大”实际上可能部分归因于心脏祖细胞对增加心脏质量的贡献。我们假设蒽环类药物减少了存活的骨髓或心脏干细胞的数量，从而严重限制了年轻心脏的生长潜力。虽然心脏驻留干细胞实际上是骨髓来源的似乎是合理的，但地幔照射加剧了蒽环类药物的心脏毒性，这一事实支持了干细胞在儿童时期就已经存在于心脏中的观点，而不是响应损伤或需求增加而迁移到那里。然而，也有可能是蒽环类药物和地幔辐射改变了心脏，使其成为骨髓或心脏源性干细胞的“敌对环境”，这些干细胞将回到损伤区域，扩增并分化为心肌细胞和心肌中的血管成分。越来越多的人认识到干细胞在心肌修复中发挥作用，包括血管结构。我们假设蒽环类药物暴露后补充干细胞可以预防迟发性心脏毒性的发生。这项研究将为DOX心脏毒性和潜在治疗提供新的认识，也可能揭示干细胞在心脏工作负荷增加反应中的作用。公共卫生相关性：蒽环类药物引起的心脏毒性作用在儿童癌症患者中是一个严重的问题，迫切需要避免这种作用。目前，对阿霉素诱导的心肌病缺乏令人满意的治疗，并且增加对蒽环类药物作用的分子机制的理解对于开发针对蒽环类药物诱导的心脏毒性的有效治疗是必要的。该提案首次建立了儿童阿霉素暴露导致成年心力衰竭的动物模型，并将评估阿霉素对心脏干细胞的影响。

DESCRIPTION (provided by applicant): While anthracyclines such as doxorubicin (DOX) are among the most effective chemotherapeutic agents and commonly used to treat pediatric cancers, they are problematic because they are associated with cardiotoxicity. With an overall survival rate for pediatric cancers of 70-90%, the number of young adults exposed to anthracyclines is steadily rising. In adults, this restricts the cumulative dose to 550mg/m2, but in children, the maximum cumulative dose must not exceed 300mg/m2. Even when treatment does not exceed this limit, heart failure can develop years after the initial exposure. Children are more vulnerable to anthracycline- induced myocardial impairment than adults, and the risk of heart failure increases the younger the age of the child at the time of anthracycline exposure. Unfortunately, heart failure may manifest years after initial exposure to anthracycline, when increased demand is placed on the heart such as during pregnancy or exercise. To understand this problem, we have established a mouse model of pediatric anthracycline cardiotoxicity and in this proposal we will investigate the mechanisms of late onset cardiotoxicity. We hypothesize that anthracyclines cause lasting damage to cardiomyocytes with resulting impaired contractile machinery or mitochondrial function. Anthracyclines exert their anti-tumor effect through negative effects on tumor angiogenesis; this is also the basis for hair loss during chemotherapy, as the vascular structures supporting the hair follicle involute. A key feature distinguishing children from adults is that the heart is still growing and must have matching angiogenesis to support the myocardium. We hypothesize that anthracyclines impair cardiac angiogenesis in the developing heart, thereby limiting the capacity to respond to increased demand, particularly as the heart grows. In light of recent work suggesting the possibility of cardiac- resident stem cells, we suggest that cardiac growth during childhood and possibly physiologic "hypertrophy" during pregnancy may actually be due in part to the contribution of cardiac progenitor cells to increasing cardiac mass. We hypothesize that anthracyclines reduce the number of surviving bone marrow or cardiac stem cells, and thereby severely limit the growth potential of the young heart. While it is plausible that cardiac resident stem cells are actually bone marrow derived, the fact that mantle irradiation exacerbates the cardiotoxicity of anthracyclines supports the idea that the stem cells are already present in the heart in childhood, rather than migrating there in response to injury or increased demand. However, it is also possible that anthracyclines and mantle irradiation alter the heart so that it is a "hostile environment" for bone marrow or cardiac-derived stem cells that would home to areas of injury, expand, and differentiate into cardiomyocytes and vascular elements in the myocardium. Stem cells are increasingly recognized to play a role in repair of the myocardium, including the vascular structures. We hypothesize that replenishing stem cells after anthracycline exposure will prevent the development of late-onset cardiotoxicity. This investigation will provide new understanding of DOX cardiotoxicity and potential therapy, and may also shed light on t role of stem cells in the response to increased cardiac workload. PUBLIC HEALTH RELEVANCE: Anthracycline-induced cardiotoxic effects are a serious problem among patients who survive childhood cancer and there is an urgent need to avoid such effects. Currently, satisfactory therapy for doxorubicin- induced cardiomyopathy is lacking and increased understanding of the molecular mechanisms of anthracycline action is necessary for the development of effective treatments against anthracycline-induced cardiotoxicity. This proposal establishes for the first time an animal model of childhood doxorubicin exposure leading to heart failure in adulthood, and will evaluate the effects of doxorubicin on cardiac stem cells.