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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 阿霉素 (DOX) 是一种高效的抗肿瘤药物，癌症患者长期使用后可导致心力衰竭。 DOX 心脏毒性的一个主要理论是活性氧 (ROS) 的产生。然而，临床试验表明抗氧化疗法的效果非常有限。该项目的目标是阐明可能独立于 ROS 的 DOX 心脏毒性的新机制。 DOX 激活心肌细胞中的泛素蛋白酶体系统 (UPS)，导致各种心脏蛋白的降解。 DOX 还会诱导大量自噬 (ATG)，这是一种自我消化机制，如果激活不当，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心脏毒性的一种新机制，抑制UPS或ATG将减少DOX引起的心脏损伤。 这些假设将通过以下具体目标进行检验：目标 1 将确定通过蛋白酶体抑制剂阻断 UPS 激活或小干扰 RNA (siRNA) 介导的蛋白酶体亚基敲低是否可以减弱 DOX 的体外和体内心脏毒性。 目标 2 将检验 ATG 激活导致 DOX 心脏毒性的假设。 我们将确定 siRNA 敲低或杂合删除 Beclin1（ATG 启动所需的基因）是否能够在体外和体内减弱 DOX 心脏毒性。 目标 3 将确定 DOX 诱导的细胞降解途径激活是否继发于氧化应激。 我们将确定通过灭活 NAD(P)H 氧化酶来减少 ROS 的产生是否可以阻止 DOX 诱导的 UPS 或 ATG 活性。