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Identifying new regulators of cardiac fibrosis and inflammation using zebrafish

使用斑马鱼识别心脏纤维化和炎症的新调节因子

基本信息

批准号：
10892436
负责人：
Juan Manuel Gonzalez-Rosa
金额：
$ 39.13万
依托单位：
BOSTON COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-22 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10892436
关键词：
Acute Adult Adverse effects Affect Alleles Animals Attenuated Cardiac Cardiac Myocytes Cicatrix Clinical Collection Competence Deposition Development Disease Disease Progression Exhibits Extracellular Matrix Feedback Fibrosis Gene Expression Profiling Gene Modified Generations Genes Genetic Models Goals Heart Heart Diseases Heart Injuries Heart failure Hypertrophy Immune Immunocompromised Host Impairment Individual Inflammasome Inflammation Inflammatory Inflammatory Response Injury Ischemia Knowledge Laboratories Link Lymphocytic Infiltrate Macrophage Mediator Modeling Molecular Mus Mutation Myocarditis NF-kappa B Natural regeneration Outcome Pathologic Pathology Persons Phase Phenotype Phosphotransferases Play Population Positioning Attribute Process Production Progressive Disease Proliferating Public Health Reperfusion Injury Reporting Research Resistance Role Serine Proteinase Inhibitors Siblings Signal Transduction Skin Syndrome System T cell infiltration T-Lymphocyte Testing Therapeutic Tissues Transgenic Organisms Translating Trypsin Inhibitors Zebrafish cardiac regeneration chemokine comparison control coronary fibrosis cost design effective therapy experimental study functional decline gain of function genetic variant inter-alpha-inhibitor loss of function mortality mutant new therapeutic target overexpression prevent recruit response tool trait transcriptomic profiling

项目摘要

Project Summary/Abstract Several cardiac diseases involve the progressive or acute loss of cardiomyocytes, which are replaced by fibrotic tissue. Cardiac fibrosis is one of the leading factors in the pathology of heart failure, a progressive disease that affects millions of people every year. Despite its recognized importance, there are no effective therapies to prevent the progression of cardiac fibrosis. Recent findings suggest that naturally occurring genetic variants protect certain individuals against the adverse changes triggered after cardiac injury, which translates into re- duced cardiac fibrosis. One of the genes that modifies the progression of disease is the cardiomyocyte-specific kinase Tnni3k. Mutations that abolish Tnni3k confer resistance to injury, and high Tnni3k levels are associated with rapid functional decline and pathological remodeling. Tnni3k is an understudied kinase, and its downstream targets and specific mechanisms by which it defines injury outcome are unknown. Our goal in this project is to identify the mechanisms linking Tnni3k levels to cardiac fibrosis. In preliminary experiments using the zebrafish as a model, we found that high levels of Tnni3k induce fibrosis deposition shortly after cardiac injury. In contrast to their wild-type siblings, animals overexpressing Tnni3k showed impaired fibrotic regression, while a newly generated tnni3k mutant exhibits minimal fibrosis after injury. Transcriptional profiling revealed that high levels of Tnni3k correlate with an exacerbated inflammatory response, markers of T-cell infiltration, and activation of all the components of the inflammasome, which are all landmarks of cardiomyocyte-induced inflammation. We also identified a potential downstream target, itih5, which has been previously reported to play a role in extracel- lular matrix stabilization in the skin. Based on our preliminary results, our central hypothesis is that Tnni3k plays a previously unappreciated role in cardiac fibrosis via modulation of inflammation, and that Itih5 is a central mediator of these effects. We will test our hypothesis in three integrative aims. In Aim 1, we will determine the role of inflammation in the development of fibrosis in response to high levels of Tnni3k. We will exploit a collection of immunocompromised zebrafish to test the contribution of specific immune populations to this excessive fibrotic response. Additionally, we will use a new cardiomyocyte specific Cas9 line to identify genes required for trigger- ing inflammation in response to high Tnni3k levels. In Aim 2, we will determine the effects of modulating Tnni3k levels pre- and post-injury on cardiac fibrosis and inflammation. We will use a new Tnni3kSWITCH line generated by our lab that will allow us to “turn off” the overexpression of Tnni3k at different times. In Aim 3, we will identify molecular regulators of scar remodeling downstream of Tnni3k. We will start by analyzing how Itih5 regulates fibrosis regression using new gain and loss of function models generated by our laboratory for this application. Collectively, these studies will establish Tnni3k and Itih5 as regulators of cardiac inflammation and fibrosis in zebrafish. We anticipate that this basic knowledge will serve as the springboard for rapid discovery of new targets to treat cardiac fibrosis in the injured heart.

项目总结/文摘