Juvenile mouse model of delayed anthracycline cardiotoxicity

项目总结/摘要 虽然蒽环类药物如阿霉素（DOX）是最有效的化疗剂之一， 它们通常用于治疗儿科癌症，但由于它们与心脏毒性有关，因此存在问题。 儿童癌症的总体存活率为70- 90%，暴露于癌症的年轻人的数量 蒽环类药物的价格在稳步上升。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， 心脏衰竭可能在初次接触后数年发生。儿童更容易受到蒽环类药物的影响- 诱发心肌损害的风险高于成年人，且年龄越小，心力衰竭的风险越大。 在蒽环类抗生素暴露的时候。不幸的是，心力衰竭可能在最初的几年后表现出来。 暴露于蒽环类药物，当心脏需求增加时，如怀孕期间，或 锻炼的为了理解这个问题，我们建立了一个小儿蒽环类药物的小鼠模型 心脏毒性，在本提案中，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损伤， 机械或线粒体功能。蒽环类药物通过对肿瘤细胞的负作用发挥其抗肿瘤作用。 肿瘤血管生成;这也是化疗期间脱发的基础，因为血管结构 支持毛囊内卷。儿童区别于成人的一个关键特征是心脏仍然是 生长并且必须具有匹配的血管生成以支持心肌。我们假设 蒽环类药物损害发育中的心脏中的心脏血管生成，从而限制了对药物的反应能力。 需求增加，特别是随着心脏的增长。根据最近的研究表明心脏病的可能性- 常驻干细胞，我们认为，心脏生长在儿童时期和可能的生理性“肥大”， 在怀孕期间，可能部分是由于心脏祖细胞的贡献， 心脏质量我们假设蒽环类药物减少了存活的骨髓或心脏细胞的数量， 干细胞，从而严重限制了年轻心脏的生长潜力。虽然心脏病可能 常驻干细胞实际上是骨髓来源的，事实上，地幔辐射加剧了 蒽环类药物的心脏毒性支持了干细胞已经存在于心脏中的观点， 儿童，而不是因受伤或需求增加而移徙到那里。但也可以 蒽环类抗生素和地幔辐射改变了心脏，使其成为骨髓的“不利环境”， 心脏来源的干细胞，可以回到损伤区域，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修复 心肌，包括血管结构。我们假设蒽环类药物治疗后补充干细胞 接触可防止发生迟发性心脏毒性。这项调查将提供新的 了解DOX心脏毒性和潜在的治疗，也可能揭示干细胞在心脏病中的作用。 对心脏工作负荷增加的反应。

Project Summary/Abstract 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 the role of stem cells in the response to increased cardiac workload.