Juvenile mouse model of delayed anthracycline cardiotoxicity

迟发性蒽环类药物心脏毒性幼年小鼠模型

• 批准号: 8402845
• 负责人: Roberta A. Gottlieb
• 金额: $ 35.23万
• 依托单位: SAN DIEGO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-19 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8402845
• 关键词: Adolescent; Adult; Age; Animal Model; Anthracyclines; Area; Blood Vessels; Blood capillaries; Bone Marrow; Bone Marrow Stem Cell; CSF3 gene; Cancer Survivor; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiotoxicity; Cell Proliferation; Child; Childhood; Development; Dose; Doxorubicin; Engraftment; Environment; Exercise; Exposure to; Failure; Growth; Growth Factor; Hair; Hair follicle structure; Heart; Heart failure; Histologic; Home environment; Homing; Hypertrophy; Impairment; In Vitro; Indium; Infarction; Injury; Insulin-Like Growth Factor I; Investigation; Left; Light; Malignant Childhood Neoplasm; Marrow; Mitochondria; Molecular; Mus; Muscle Cells; Myocardial; Myocardium; Pathologic; Patients; Physiological; Play; Pregnancy; Risk; Role; Stem cells; Structure; Survival Rate; Therapeutic; Time; Tumor Angiogenesis; Ventricular; Work; Workload; abstracting; angiogenesis; base; capillary; cardiac repair; chemotherapeutic agent; chemotherapy; density; effective therapy; in vivo; irradiation; mouse model; prevent; repaired; response; response to injury; senescence; stem cell population; stem cell therapy; tumor; young adult

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.

项目总结/文摘

项目成果

Chemotherapy and cardiotoxicity.

化疗和心脏毒性。

• 发表时间: 2008
• 期刊: Reviews in cardiovascular medicine
• 影响因子: 2.7
• 作者: Broder,Howard;Gottlieb,RobertaA;Lepor,NormanE
• 通讯作者: Lepor,NormanE

Mitochondria and mitophagy: the yin and yang of cell death control.

• DOI: 10.1161/circresaha.112.265819
• 发表时间: 2012-10-12
• 期刊: Circulation research
• 影响因子: 20.1
• 作者: Kubli DA;Gustafsson ÅB
• 通讯作者: Gustafsson ÅB

Bnip3 as a dual regulator of mitochondrial turnover and cell death in the myocardium.

• DOI: 10.1007/s00246-010-9876-5
• 发表时间: 2011-03
• 期刊: PEDIATRIC CARDIOLOGY
• 影响因子: 1.6
• 作者: Gustafsson, Asa B.

Regulation of autophagy by metabolic and stress signaling pathways in the heart.

• DOI: 10.1097/fjc.0b013e318256cdd0
• 发表时间: 2012-08
• 期刊: Journal of cardiovascular pharmacology
• 影响因子: 3
• 作者: Lee Y;Lee HY;Gustafsson AB
• 通讯作者: Gustafsson AB

Cell death in the myocardium: my heart won't go on.

• DOI: 10.1002/iub.1180
• 发表时间: 2013-08
• 期刊: IUBMB LIFE
• 影响因子: 4.6
• 作者: Orogo, Amabel M.;Gustafsson, Asa B.
• 通讯作者: Gustafsson, Asa B.