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Managing Cardiac Toxicities of Cancer Therapy

管理癌症治疗的心脏毒性

基本信息

批准号：
10322167
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
项目类别：
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/10322167
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 Work cancer therapy cell type chemotherapy cofilin 2 design heart function interstitial ischemic injury mitochondrial oxidative dysfunction myocardial injury novel oxidation preservation prevent programs

项目摘要

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.

项目总结