Coordination of inflammatory signaling and cardiac fibrosis by small proline rich proteins

富含脯氨酸的小蛋白协调炎症信号传导和心脏纤维化

基本信息

批准号：
10063897
负责人：
Eric M Small
金额：
$ 42.52万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-21 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10063897
关键词：
Address Advanced Development Antineoplastic Agents Binding Biological Assay CRISPR/Cas technology Cancer Biology Cardiac Cardiac development Cardiology Cell Cycle Cell Therapy Chromatin Cicatrix Clinical Trials Complex Data Deposition Disease Event Exercise Fibroblasts Gene Expression Gene Expression Regulation Gene Proteins Genes Genetic Transcription Health Heart Heart failure Human In Vitro Inflammatory Inflammatory Response Insulin-Like Growth Factor I Investigation Link Literature MDM2 gene Mediating Molecular Mus Mutate Mutation Myocardial Infarction Myocardium Myofibroblast Nuclear Pathologic Patients Phenotype Process Proteins Quality of life Reactive Oxygen Species Regulation Regulatory Element Role SPRR1A Signal Transduction Sudden Death TNF Receptor-Associated Factors TP53 gene TRAF2 gene Testing Therapeutic Tissues Transcriptional Regulation Ubiquitin Ubiquitination base coronary fibrosis defined contribution experimental study genome editing heart function human disease improved in vivo mouse model novel novel therapeutic intervention proline-rich proteins protein degradation small molecule stem cells ubiquitin-protein ligase

项目摘要

PROJECT SUMMARY Cardiac fibroblasts (CF) contribute to the inflammatory response and subsequent scar formation following myocardial infarction (MI); however, the mechanisms coordinating these processes are poorly understood. Using mouse models and human heart tissue, we have found that Small proline rich proteins (Sprr) are uniquely expressed in CF, and are among the most upregulated genes during disease. Conversely, Sprr gene expression is extinguished in CF during exercise. Our preliminary data reveals that SPRR2B binds USP7 and regulates USP7 / MDM2 - E3 ubiquitin ligase substrate selection, facilitating p53 ubiquitination and degradation and relieving constraints on CF accumulation in disease. In contrast, SPRR1A harbors an interaction motif for tumor necrosis factor (TNF) receptor-associated factor (TRAF)-2, an E3 ubiquitin ligase that controls inflammatory signaling. Based on our preliminary data and supporting literature, we hypothesize that context dependent control of E3 ubiquitin-ligase substrate selection by SPRR1A and SPRR2B modulates the inflammatory response following an ischemic event and drives the accumulation of pathological CF, which results in cardiac fibrosis and the progression of HF. A corollary to this hypothesis is that novel MDM2-E3 ubiquitin ligase antagonists, currently in clinical trials as anti-cancer agents, may be useful for the treatment of cardiac fibrosis. Here, we propose the following aims to define a transcriptional paradigm of CF gene regulation in health and disease, and elucidate a novel and druggable mechanism of E3 ubiquitin ligase substrate selection in CF that coordinates the inflammatory response and the development of cardiac fibrosis. If successful, the proposed experiments will refine our understanding of the molecular mechanisms that drive cardiac fibrosis and the progression of HF. Our study may also uncover a novel mechanism of ubiquitin-mediated protein degradation that is broadly applicable to the fields of cardiology, progenitor cell-based therapeutics, and cancer biology and further efforts to harness novel E3-ubiquitin ligase antagonists for therapeutic benefit.

项目摘要心脏成纤维细胞（CF）有助于炎症反应和随后的疤痕形成。心肌梗塞（MI）；但是，协调这些过程的机制知之甚少。使用小鼠模型和人类心脏组织，我们发现富含脯氨酸的小蛋白（SPRR）是独特的在CF中表达，是疾病期间最上调的基因之一。相反，sprr基因表达运动过程中的CF熄灭。我们的初步数据表明，SPRR2B绑定USP7并调节 USP7 / MDM2 -E3泛素连接酶底物选择，促进p53泛素化和降解，减轻对CF疾病积累的限制。相比之下，sprr1a具有肿瘤的相互作用图案坏死因子（TNF）受体相关因子（TRAF）-2，一种控制炎症的E3泛素连接酶信号。基于我们的初步数据和支持文献，我们假设该上下文取决于通过SPRR1A和SPRR2B选择E3泛素 - 连接酶底物的选择可调节炎症缺血事件后的反应并驱动病理CF的积累，这导致心脏纤维化和HF的进展。这种假设的推论是新型的MDM2-E3泛素该连接酶拮抗剂目前正在临床试验中作为抗癌药，可能对心脏治疗有用纤维化。在这里，我们提出以下旨在定义健康中CF基因调节的转录范式和疾病，并阐明了CF中E3泛素连接酶底物选择的新型和可毒的机制这协调炎症反应和心脏纤维化的发展。如果成功，提议实验将完善我们对驱动心脏纤维化的分子机制和 HF的进展。我们的研究还可能发现泛素介导的蛋白质降解的新型机制这广泛适用于心脏病学领域，基于祖细胞的疗法和癌症生物学以及进一步努力利用新型E3泛素连接酶拮抗剂为治疗益处。