SD COBRE: NOVEL MECHANISMS OF DOXORUBIN-INDUCED HEART FAILURE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 阿霉素(DOX)是一种高效的抗肿瘤药物，在癌症患者长期使用后会导致心力衰竭。DOX心脏毒性的一个主要理论是产生活性氧物种(ROS)。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DOX心脏毒性的新机制，这些机制可能独立于ROS。DOX激活心肌细胞内的泛素-蛋白酶体系统(UPS)，导致多种心肌蛋白的降解。DOX还诱导大量自噬(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。我们推测，UPS和ATG的异常激活是DOX心脏毒性的新机制，抑制UPS或ATG将减轻DOX所致的心脏损伤。这些假说将通过以下具体目标进行检验：Aim 1将确定通过蛋白酶体抑制剂或小干扰RNA(SiRNA)介导的蛋白酶体亚基敲除UPS激活是否可以在体外和体内减轻DOX的心脏毒性。目的2将验证ATG激活导致DOX心脏毒性的假设。我们将确定siRNA敲除或杂合性缺失Beclin1基因是否能够在体外和体内减轻DOX的心脏毒性。Beclin1是启动ATG所需的基因。目的3将确定DOX诱导的细胞降解途径的激活是否次于氧化应激。我们将确定通过灭活NAD(P)H氧化酶来减少ROS的产生是否可以阻断DOX诱导的UPS或ATG活性。

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.