SD COBRE: NOVEL MECHANISMS OF DOXORUBIN-INDUCED HEART FAILURE

SD COBRE：阿霉素诱发心力衰竭的新机制

• 批准号: 8168338
• 负责人: Qiangrong Liang
• 金额: $ 29.62万
• 依托单位: SANFORD RESEARCH/USD
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8168338
• 关键词: Adriamycin PFS; Attenuated; Autophagocytosis; Cancer Patient; Cardiac; Cardiac Myocytes; Cardiotoxicity; Cell Death; Chronic; Clinical Trials; Computer Retrieval of Information on Scientific Projects Database; Degradation Pathway; Digestion; Doxorubicin; Funding; Generations; Genes; Goals; Grant; Heart failure; In Vitro; Injury; Institution; Mediating; Oxidases; Oxidative Stress; Production; Proteasome Inhibitor; Proteins; Reactive Oxygen Species; Research; Research Personnel; Resources; Secondary to; Small Interfering RNA; Source; System; Testing; Ubiquitin; United States National Institutes of Health; antioxidant therapy; antitumor agent; in vivo; multicatalytic endopeptidase complex; novel; theories

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Doxorubicin (DOX) is a highly effective antitumor agent that can cause heart failure after chronic use in cancer patients. A major theory for DOX cardiac toxicity is the generation of reactive oxygen species (ROS). However, clinical trials have shown very limited effect of antioxidant therapy. The goal of this project is to elucidate novel mechanisms of DOX cardiotoxicity that may be independent of ROS. DOX activates the ubiquitin-proteasome system (UPS) in cardiomyocytes, leading to the degradation of various cardiac proteins. DOX also induces massive autophagy (ATG), a self-digestion mechanism that may cause autophagic cell death if activated inappropriately. We hypothesize that abnormal activation of the UPS and ATG is a novel mechanism of DOX cardiotoxicity, and that inhibition of UPS or ATG will reduce DOX-induced cardiac injury. These hypotheses will be tested by the following specific aims: Aim 1 will determine if blockade of UPS activation by a proteasome inhibitor or small interfering RNA (siRNA)-mediated knockdown of proteasomal subunits can attenuate DOX cardiotoxicity in vitro and in vivo. Aim 2 will test the hypothesis that activation of ATG contributes to DOX cardiotoxicity. We will determine if siRNA knockdown or heterozygous deletion of Beclin1, a gene required for ATG initiation, is able to attenuate DOX cardiotoxicity in vitro and in vivo. Aim 3 will determine if DOX-induced activation of cellular degradation pathways is secondary to oxidative stress. We will determine if reducing ROS production by inactivating NAD(P)H oxidase can block DOX-induced UPS or ATG activity.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 阿霉素（DOX）是一种高效的抗肿瘤剂，可在癌症患者长期使用后引起心力衰竭。 DOX心脏毒性的主要理论是活性氧（ROS）的产生。但是，临床试验显示抗氧化剂治疗的作用非常有限。该项目的目的是阐明可能独立于ROS的DOX心脏毒性的新型机制。 DOX激活心肌细胞中的泛素蛋白酶体系统（UPS），导致各种心脏蛋白质降解。 DOX还诱导了巨大的自噬（ATG），这是一种自消化机制，如果不恰当地激活，可能会导致自噬细胞死亡。 我们假设UPS和ATG的异常激活是DOX心脏毒性的新机制，并且对UPS或ATG的抑制作用将减少DOX诱导的心脏损伤。 这些假设将通过以下特定目的进行测试：AIM 1将确定蛋白酶体抑制剂或小干扰RNA（siRNA）介导的蛋白酶体亚基的敲低是否可以减弱体外和体内的蛋白酶体亚基的敲低。 AIM 2将检验以下假设：ATG的激活有助于DOX心脏毒性。 我们将确定siRNA敲低或杂合缺失Beclin1（ATG启动所需的基因）是否能够在体外和体内衰减DOX心脏毒性。 AIM 3将确定DOX诱导的细胞降解途径的激活是否继发于氧化应激。 我们将通过灭活NAD（P）H氧化酶可以阻止DOX诱导的UPS或ATG活性来确定减少ROS产生。