Managing Cardiac Toxicities of Cancer Therapy

管理癌症治疗的心脏毒性

• 批准号: 10536688
• 负责人: Fadi N Salloum
• 金额: $ 77.63万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10536688
• 关键词: Acute myocardial infarction; Attenuated; Blood; Cancer Survivor; Cardiac; Cardiomyopathies; Cardiotoxicity; Cell Death; Cellular Stress; Data; Development; Doxorubicin; Exposure to; Failure; Fibrosis; Foundations; Goals; Heart; Heart failure; Hydrogen Sulfide; Inflammasome; Inflammation; Inflammatory; Injury; Investigation; Ischemia; Knowledge; Literature; Malignant Neoplasms; Mediating; Modality; Mus; Myocardial Infarction; Myocardial Ischemia; Myocarditis; Nitric Oxide; Oncology; Oral; Oxidative Stress; Patients; Phase I Clinical Trials; Post-Translational Protein Processing; Pre-Clinical Model; Preventive; Process; Production; Proteins; Role; Secondary to; Signal Pathway; Signal Transduction; Sterility; Stress; Structural Protein; Therapeutic; Toxic effect; Work; cancer therapy; cell type; chemotherapy; cofilin; cofilin 2; design; heart function; interstitial; ischemic injury; mitochondrial dysfunction; myocardial injury; novel; oxidation; preservation; prevent; programs

Project Summary This R35 application proposes to capitalize on previous work produced by the PI over the past 11 years and to further serve as a strong foundation for interrogating the role of sterile cardiac inflammation (inflammasomes) in promoting the progression of heart failure caused by chemotherapy-induced cardiotoxicity and complicated with myocardial ischemia. The overarching goal of this program is to better understand how inflammasome formation/activation in the heart secondary to different stress signals perpetuates myocardial injury and also dissect the contributions of different cardiac cell types during this pathophysiologic process. 1) Previous studies from the PI’s lab have characterized the role of the inflammasome in mediating adverse cardiac remodeling following acute myocardial infarction in preclinical models. 2) Other studies from the PI’s lab also demonstrated that NLRP3 inflammasome inhibition reduced interstitial fibrosis and preserved systolic cardiac function in mice exposed to doxorubicin. Evidence from the literature also supports a pathophysiologic role of NLRP3 in mediating doxorubicin-induced cardiotoxicity. Moreover, studies from the PI’s lab and others have shown that endogenous production of hydrogen sulfide (H2S) is essential for survival during cellular stresses, including ischemia, and that administration of H2S donors further promotes survival. The orally-active H2S- donor SG1002 was shown in a recent Phase I clinical trial to be safe and tolerable in heart failure patients and also to increase blood H2S levels as well as circulating nitric oxide while attenuating BNP. We recently demonstrated that H2S treatment attenuates ischemic and inflammatory (NLRP3 inflammasome) injury following myocardial infarction. Accordingly, modulation of the inflammasome with H2S may represent an important mechanism to limit inflammatory cell death and mitigate cardiomyopathy. Preliminary data demonstrate that increases in cofilin-2 expression and its potential for phospohorylation and oxidation under oxidative stress rises during ischemic injury, which is attenuated with H2S donors. Thus, this proposal provides the opportunity to perform in-depth investigations on role of the cardiac inflammasome and structural proteins, such as cofilin2, in heart failure due to chemotoxicity and also when complicated with myocardial infarction, therefore extending our knowledge on the potential mechanism of cardiotoxicity and facilitating the design and development of novel preventive/therapeutic modalities in the emerging field of cardio-oncology.

项目摘要 本R35申请建议利用PI在过去11年中所做的工作， 进一步作为询问无菌心脏炎症（炎性小体）作用的坚实基础 在促进由化疗诱导的心脏毒性和并发症引起的心力衰竭的进展方面， 心肌缺血该计划的首要目标是更好地了解炎症如何 心脏中继发于不同应激信号的形成/激活使心肌损伤持续存在， 解剖不同类型的心肌细胞在这一病理生理过程中的作用。1)先前 PI实验室的研究已经表征了炎性小体在介导不良心脏反应中的作用， 临床前模型中急性心肌梗死后的重构。2)PI实验室的其他研究也 结果表明，NLRP 3炎性体抑制减少了间质纤维化，并保护了心脏收缩功能。 在暴露于阿霉素的小鼠中的功能。来自文献的证据也支持了 NLRP 3介导阿霉素诱导的心脏毒性。此外，PI实验室和其他机构的研究表明， 显示硫化氢（H2S）的内源性产生对于细胞应激期间的存活是必需的， 包括局部缺血，并且施用H2S供体进一步促进存活。口服活性H2S- 供体SG 1002在最近的I期临床试验中显示在心力衰竭患者中是安全和可耐受的， 还增加血液H2S水平以及循环一氧化氮，同时减弱BNP。我们最近 表明H2S处理减弱缺血性和炎性（NLRP 3炎性体）损伤 心肌梗死后。因此，用H2S调节炎性小体可能代表了一种新的治疗方法。 限制炎性细胞死亡和减轻心肌病的重要机制。初步数据 证明了cofilin-2表达的增加及其磷酸化和氧化的潜力， 氧化应激在缺血性损伤期间升高，其被H2S供体减弱。因此，该提案提供了 有机会对心脏炎性小体和结构蛋白的作用进行深入研究， 例如cofilin 2，在由于化学毒性引起的心力衰竭中以及在并发心肌梗塞时， 因此扩展了我们对心脏毒性潜在机制的了解，并促进了设计， 在新兴的心脏肿瘤学领域开发新的预防/治疗方式。