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 这项R35申请提案要利用PI在过去11年中生产的先前工作，并 进一步是询问无菌心脏感染作用（炎症）的强大基础 在促进由化学疗法引起的心脏毒性引起的心力衰竭进展和复杂 与心肌缺血。该计划的总体目标是更好地了解炎症 在不同的压力信号继发的心脏中形成/激活会使心肌损伤永存，也使 在这种病理生理过程中剖析不同心脏细胞类型的贡献。 1）以前 PI实验室的研究表征了炎症体在介导不良心脏中的作用 临床前模型中急性心肌梗塞后进行重塑。 2）PI实验室的其他研究也 证明NLRP3炎性体抑制减少了间质纤维化并保留了收缩期心脏 暴露于阿霉素的小鼠的功能。文献的证据还支持 介导阿霉素诱导的心脏毒性中的NLRP3。此外，PI实验室的研究和其他研究 表明，内源性硫化氢（H2S）对于在细胞应激期间存活至关重要， 包括缺血，以及H2S捐赠者的给药进一步促进生存。口服活跃的H2S- 在最近的I期临床试验中显示了供体SG1002，该试验在心力衰竭患者中是安全可容忍的，并且 同时还可以增加血液H2S水平，并在衰减BNP的同时循环一氧化氮。我们最近 证明H2S治疗减弱了缺血性和炎症（NLRP3炎性体）损伤 遵循心肌梗塞。根据所有人，使用H2S的炎性体调节可能代表 限制炎症细胞死亡并减轻心肌病的重要机制。初步数据 证明cofilin-2表达的增加及其在凤凰化和氧化下的潜力 缺血性损伤期间氧化应激升高，该缺血性损伤被H2S供体衰减。那就是这个建议提供的 对心脏炎症体和结构蛋白的作用进行深入研究的机会， 例如cofilin2，由于介毒性而引起的心力衰竭，并且在与心肌梗死复杂时， 因此，扩展了我们对心脏毒性潜在机制的了解，并促进了设计和 在心脏肿瘤学领域的新型预防/治疗方式的发展。