Cellular Senescence: A Novel Mechanism of Doxorubicin-Induced Cardiotoxicity

细胞衰老：阿霉素诱导心脏毒性的新机制

基本信息

批准号：
10589889
负责人：
Giselle C Melendez
金额：
$ 11.7万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10589889
关键词：
Active Learning Adjuvant Therapy Adult Affect Anthracycline Antineoplastic Agents Area Bioenergetics Biogenesis Biology Breast Cancer Treatment Cardiac Cardiac Myocytes Cardiotoxicity Cardiovascular system Cell Aging Cell Death Cell Proliferation Cells Collagen Culture Techniques DNA Damage Data Development Doxorubicin Educational workshop Electron Transport Exposure to Extracellular Matrix Extracellular Matrix Proteins Fibroblasts Fibrosis Funding Genes Goals Heart failure Homidium Bromide In Vitro Individual Inflammatory Injury K-Series Research Career Programs Left Ventricular Dysfunction Left Ventricular Function Left ventricular structure Link Lymphoma Magnetic Resonance Malignant Neoplasms Mass Spectrum Analysis Measures Mentors Mitochondria Mitochondrial DNA Modeling Molecular Morbidity - disease rate Myofibroblast Nature Pathogenesis Patients Peptide Hydrolases Phenotype Production Proteins Proteomics Rattus Reactive Oxygen Species Research Research Personnel Role Science Senior Scientist Symptoms Teacher Professional Development Therapeutic Tissues Toxic effect Training Treatment Protocols autocrine biological adaptation to stress career career development cell type chemokine chemotherapy clinically relevant coronary fibrosis cytokine cytotoxic design experimental study in vivo leadership development leukemia member migration mitochondrial dysfunction novel paracrine premature prevent sarcoma senescence skills success treatment strategy tumor virtual

项目摘要

Project Summary Traditionally, cardiotoxic effects in patients undergoing anthracycline-based chemotherapy (Anth-bC) are attributed to cardiomyocyte injury due to DNA damage and altered mitochondrial bioenergetics leading to excess reactive oxygen species and cell death. As a result, most research and treatment strategies are directed towards preventing cardiomyocyte injury. Recently, evidence from our group demonstrates that cardiac fibrosis also contributes to left ventricular dysfunction and heart failure symptoms following Anth-bC and now we have evidence that doxorubicin (Dox, a widely used Anth-bC) has a direct effect on cardiac fibroblasts to produce excess collagen. This project focuses on a candidate underlying mechanism by which Dox promotes cardiac fibroblasts activation and fibrosis: a stress response known as cellular senescence. Cellular senescence is characterized by permanent arrest of cell proliferation, mitochondrial dysfunction and development of a senescence-associated secretory phenotype (SASP) producing inflammatory cytokines, chemokines and proteases with both autocrine and paracrine effects. Although senescence has been studied in multiple cell types, there are virtually no data on senescence in adult cardiac fibroblasts. We have now evidence that cardiac fibroblasts exposed to Dox indeed develop mitochondrial dysfunction and become prematurely senescent. However, even in well studied cell types a complete understanding of the SASP secretome and the exact nature of the relationship between mitochondrial dysfunction and the senescence phenotype remain unclear. We propose to use isolated adult rat cardiac fibroblasts and a clinically relevant rat model of cardiotoxicity to critically determine the role of the secretome constituents in the activation of cardiac fibroblasts and the role mitochondrial dysfunction in the development of senescence and its association to cardiac fibrosis and left ventricular dysfunction. Our specific aims are designed to answer the following questions: 1) What are the proteomic constituents of the cardiac fibroblast secretome induced by Dox that stimulate a pro-fibrotic phenotype; 2) is there a causal role for mitochondria dysfunction in the development of Dox-induced senescence and SASP?; and 3) to what extent cardiac fibroblasts senescence, SASP and mitochondrial dysfunction are associated with the establishment and progression of myocardial fibrosis and LV dysfunction in vivo. Through the accomplishment of these significant aims, this project will train the PI in new areas of mass spectrometry-based proteomics, mitochondrial function and senescence biology. This training includes workshops in proteomics, experiential learning and development of leadership skills. Ultimately, this will lead to the success of her long term goal of becoming an independent funded investigator significantly contributing to the understanding of the molecular and cellular causes of the cardiovascular toxicities of chemotherapeutics that can be targeted to prevent and/or mitigate cardiovascular morbidities induced by these therapies.

项目摘要传统上，接受基于蒽环类化疗（ANTH-BC）的患者的心脏毒性作用是归因于由于DNA损伤而导致的心肌细胞损伤和线粒体生物能的改变导致过量活性氧和细胞死亡。结果，大多数研究和治疗策略都是针对的防止心肌细胞损伤。最近，我们小组的证据表明心脏纤维化也在ANTH-BC之后导致左心室功能障碍和心力衰竭症状，现在我们已经有了阿霉素（DOX，一种广泛使用的ANTH-BC）对心脏成纤维细胞有直接作用以产生的证据多余的胶原蛋白。该项目着重于DOX促进心脏的候选机制的基本机制成纤维细胞激活和纤维化：一种称为细胞衰老的应激反应。细胞衰老是以永久性停止细胞增殖，线粒体功能障碍和发展的特征与衰老相关的分泌表型（SASP）产生炎症细胞因子，趋化因子和具有自分泌和旁分泌作用的蛋白酶。尽管已经在多个细胞中研究了衰老类型，几乎没有成年心脏成纤维细胞衰老的数据。我们现在有证据表明心脏暴露于DOX的成纤维细胞确实会出现线粒体功能障碍并过早衰老。但是，即使在经过良好研究的细胞类型中，也完全了解SASP Sextome和确切的性质线粒体功能障碍与衰老表型之间的关系尚不清楚。我们建议使用孤立的成年大鼠心脏成纤维细胞和临床相关的心脏毒性大鼠模型确定分泌组成分在心脏成纤维细胞激活中的作用和线粒体的作用衰老发展及其与心脏纤维化的关联的功能障碍和左心室功能障碍。我们的具体目的旨在回答以下问题：1）蛋白质组学是什么由DOX引起的心脏成纤维细胞分泌组成的成分，刺激了促纤维化表型； 2）是线粒体功能障碍在DOX诱导的衰老和SASP的发展中具有因果作用？ 3）在多大程度上，心脏成纤维细胞衰老，SASP和线粒体功能障碍与体内心肌纤维化和LV功能障碍的建立和进展。通过实现这些重要目标，该项目将在新的大众领域训练PI 基于光谱法的蛋白质组学，线粒体功能和衰老生物学。该培训包括蛋白质组学的讲习班，经验学习和领导能力的发展。最终，这将导致她成为一名独立资助的调查员的长期目标的成功，很大程度上有助于对化学治疗剂心血管毒性的分子和细胞原因的理解可以针对这些疗法引起的预防和/或减轻心血管病变。