Managing Cardiac Toxicities of Cancer Therapy

项目摘要 此R35应用程序建议利用PI在过去11年中所做的工作，并 进一步作为询问无菌心脏炎症(炎性小体)的作用的坚实基础 在促进化疗所致心力衰竭进展中的心脏毒性和并发症 并伴有心肌缺血。这个项目的首要目标是更好地了解炎症是如何 心脏中继发于不同应激信号的形成/激活会使心肌损伤持续存在，而且 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)上一次 PI实验室的研究已经确定了炎性小体在调节心脏不良反应中的作用 临床前模型中急性心肌梗死后的重塑。2)PI实验室的其他研究也 证明抑制NLRP3炎性小体可减少间质纤维化并保护心脏收缩功能 阿霉素对小鼠功能的影响。文献中的证据也支持一种病理生理学作用 NLRP3在介导阿霉素心脏毒性中的作用此外，来自PI实验室和其他人的研究已经 研究表明，在细胞应激状态下，内源性硫化氢的产生是生存所必需的。 包括缺血，而且硫化氢捐赠者的管理进一步提高了存活率。口服活性硫化氢- 供体SG1002在最近的一项I期临床试验中被证明对心力衰竭患者是安全和耐受的， 在降低BNP的同时，还可以提高血液中的硫化氢水平和循环中的一氧化氮水平。我们最近 证明硫化氢治疗减轻缺血和炎症性(NLRP3炎症小体)损伤 在心肌梗死后。因此，用硫化氢对炎症体的调制可以代表一种 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COFILIN-2的表达增加及其在磷酸化和氧化中的潜力 氧化应激在缺血损伤过程中升高，而硫化氢供体可减轻氧化应激。因此，这项提案提供了 有机会对心脏炎症小体和结构蛋白的作用进行深入研究， 例如Cofilin2，在由于化学毒性引起的心力衰竭中，以及当合并心肌梗死时， 因此，扩大了我们对心脏毒性潜在机制的了解，并促进了设计和 在新兴的心脏肿瘤学领域开发新的预防/治疗模式。

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.