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.

项目概要传统上，接受蒽环类化疗 (Anth-bC) 的患者的心脏毒性作用是归因于 DNA 损伤和线粒体生物能改变导致心肌细胞损伤，导致过量活性氧和细胞死亡。因此，大多数研究和治疗策略都针对防止心肌细胞损伤。最近，我们小组的证据表明，心脏纤维化也 Anth-bC 后会导致左心室功能障碍和心力衰竭症状，现在我们有有证据表明阿霉素（Dox，一种广泛使用的 Anth-bC）对心脏成纤维细胞产生直接影响多余的胶原蛋白。该项目重点关注 Dox 促进心脏功能的候选潜在机制成纤维细胞活化和纤维化：一种称为细胞衰老的应激反应。细胞衰老是其特点是细胞增殖永久停滞、线粒体功能障碍和衰老相关分泌表型（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。尽管衰老已经在多个细胞中进行了研究类型，实际上没有关于成人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阿霉素的成纤维细胞确实会出现线粒体功能障碍并过早衰老。然而，即使在经过充分研究的细胞类型中，也无法完全了解 SASP 分泌组及其确切性质线粒体功能障碍与衰老表型之间的关系仍不清楚。我们提议使用分离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来危重确定分泌组成分在心脏成纤维细胞激活中的作用以及线粒体的作用衰老发展过程中的功能障碍及其与心脏纤维化和左心室的关系功能障碍。我们的具体目标旨在回答以下问题：1）什么是蛋白质组学？ Dox 诱导的心脏成纤维细胞分泌组的成分刺激促纤维化表型； 2) 是线粒体功能障碍在 Dox 诱导的衰老和 SASP 的发展中是否存在因果关系？ 3) 心脏成纤维细胞衰老、SASP 和线粒体功能障碍在多大程度上与体内心肌纤维化和左心室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对 PI 进行培训基于光谱分析的蛋白质组学、线粒体功能和衰老生物学。本次培训内容包括蛋白质组学、体验式学习和领导技能发展研讨会。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极大地促进了了解化疗药物心血管毒性的分子和细胞原因可以有针对性地预防和/或减轻这些疗法引起的心血管疾病。