Juvenile mouse model of delayed anthracycline cardiotoxicity

描述(申请人提供)：虽然多柔比星(DOX)等蒽环类药物是最有效的化疗药物之一，通常用于治疗儿童癌症，但它们存在问题，因为它们与心脏毒性有关。由于儿童癌症的总体存活率为70%-90%，接触蒽环类药物的年轻人数量正在稳步上升。在成人，这将累积剂量限制在550毫克/平方米，但在儿童，最大累积剂量不得超过300毫克/平方米。即使治疗没有超过这一限制，心力衰竭也可能在最初暴露数年后发生。儿童比成年人更容易受到蒽环类药物引起的心肌损伤的影响，而且在儿童接触蒽环类药物时，年龄越小，心力衰竭的风险就越大。不幸的是，当对心脏的需求增加时，例如在怀孕或锻炼期间，最初接触蒽环类药物数年后可能会出现心力衰竭。为了了解这一问题，我们建立了一种儿童蒽环类药物心脏毒性的小鼠模型，在这项建议中，我们将研究迟发性心脏毒性的机制。我们假设，蒽环类药物会对心肌细胞造成持久的损伤，从而导致收缩机械或线粒体功能受损。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内卷。儿童与成人区别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，在发育中的心脏中，蒽环类药物会损害心脏血管的生成，从而限制了对增加的需求做出反应的能力，特别是随着心脏的生长。鉴于最近的研究表明心脏干细胞存在的可能性，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前体细胞对心脏质量增加的贡献。我们假设，蒽环类药物会减少存活的骨髓或心脏干细胞的数量，从而严重限制年轻心脏的生长潜力。虽然心脏常驻干细胞实际上可能来自骨髓，但外套膜辐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存在于心脏中的观点，而不是因损伤或需求增加而迁移到那里。然而，蒽环类药物和外套膜辐射也有可能改变心脏，使其成为骨髓或心脏来源干细胞的“恶劣环境”，这些干细胞将在心肌中聚集受损区域，扩张并分化为心肌细胞和血管成分。干细胞在包括血管结构在内的心肌修复中发挥着越来越重要的作用。我们假设，在暴露于蒽环类药物后补充干细胞将防止迟发性心脏毒性的发生。这项研究将提供对DOX心脏毒性和潜在治疗的新理解，并可能阐明干细胞在心脏负荷增加的反应中所起的作用。公共卫生相关性：在儿童癌症患者中，蒽环类药物引起的心脏毒性作用是一个严重的问题，迫切需要避免这种影响。目前，对阿霉素所致心肌病的治疗尚缺乏令人满意的治疗方法，需要进一步了解其作用的分子机制，以开发有效的治疗手段来对抗其心脏毒性。这项建议首次建立了儿童时期接触阿霉素导致成年后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.