Regulation of TRAF2-Dependent Inflammatory Signaling by Small Proline Rich Protein 1A in the Myocardium

心肌中富含脯氨酸的小蛋白 1A 对 TRAF2 依赖性炎症信号的调节

• 批准号: 10375803
• 负责人: Kimberly Nicole Burgos Villar
• 金额: $ 4.68万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-07 至 2024-01-06
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10375803
• 关键词: Acute; Address; Affect; Apoptosis; Area; Binding Sites; Biological Assay; Blood; Blood Vessels; Cardiac; Cardiac Myocytes; Cause of Death; Cell Death; Cell Survival; Cell membrane; Cells; Cessation of life; Characteristics; Chronic; Cicatrix; Co-Immunoprecipitations; Complex; Coronary; Coronary artery; Data; Disease; Echocardiography; Etiology; Exhibits; Exposure to; Extracellular Matrix; Family; Feedback; Fibroblasts; Fibrosis; Flow Cytometry; Functional disorder; Gene Expression; Gene Expression Profiling; Genes; Genetic Transcription; Heart; Heart failure; Hypertension; Hypertrophy; Immune; Immune response; Immunohistochemistry; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; Investigation; Ischemia; Label; Left ventricular structure; Ligation; Literature; Mus; Myocardial Infarction; Myocardium; Necrosis; Obstruction; Pathologic; Pathologic Processes; Pathway interactions; Phase; Physiology; Play; Polymerase Chain Reaction; Process; Protein Family; Proteins; Pump; Regulation; Reporting; Resolution; Response to stimulus physiology; Role; SPRR1A; Signal Pathway; Signal Transduction; TNF Receptor-Associated Factors; TRAF2 gene; Time; Troponin T; Tumor Necrosis Factor Receptor; Tumor-infiltrating immune cells; Ubiquitin; Ubiquitination; Up-Regulation; Western Blotting; adeno-associated viral vector; adenoviral-mediated; cardiac repair; cardioprotection; cytokine; differential expression; experience; experimental study; genetic signature; healing; heart function; in vivo; knock-down; member; multicatalytic endopeptidase complex; negative affect; novel; overexpression; pressure; proline-rich proteins; promoter; recruit; repaired; response; response to injury; therapeutic development; transcriptome sequencing; ubiquitin-protein ligase

ABSTRACT: Heart failure (HF) is a leading cause of death worldwide and defined by an inability of the heart to pump sufficient blood throughout the body. HF can be induced by persistent conditions such as high blood pressure, or by acute injuries such as myocardial infarction (MI). MI is characterized by the obstruction of a coronary blood vessel resulting in ischemia. Cardiomyocytes (CMs) affected by the ischemia undergo necrosis and apoptosis. To clear the resulting cellular debris, immune cells infiltrate the area while resident fibroblasts begin to secrete an extracellular matrix-rich scar to maintain the structural integrity of the heart. This eloquent response is essential to overcoming the initial injury, and exaggeration of any particular phase can have detrimental effects. While the etiology of disease associated with high blood pressure and MI are unique, they share similar features such as hypertrophy, inflammation, and fibrosis. To better understand the process of pathological cardiac remodeling, we performed RNA-sequencing to identify transcriptional gene expression profiles associated with pathologic fates. We identified a family of small proline-rich proteins (SPRRs) that are differentially regulated in disease; Sprr1a is highly upregulated in response to inflammatory cytokines in CFs and CMs in the border zone (BZ) after MI. Preliminary data suggests a predicted binding site between SPRR1A and tumor necrosis factor (TNF) receptor associated factor (TRAF)2, an E3 ubiquitin ligase that acts in response to the TNF receptor at the plasma membrane to propagate inflammatory signaling. Further investigation has led us to hypothesize that SPRR1A is altering the ubiquitination status or proteasome function in CMs to halt pro-inflammatory signaling and allow for the increase in inflammation-resolution pathways to occur. Separately, SPRR1A and TRAF2 may also be playing a role in the rate of cell survival along the border of injury. Understanding the coordination of the healing response following MI will build the basis needed for further therapeutic developments. This proposal aims to determine the novel in vitro mechanism of action and associated in vivo complications associated with the modulation of SPRR1A expression.

抽象的： 心力衰竭（HF）是全世界死亡的主要原因，并因心脏无法充分泵送而定义 整个身体的血液。 HF可以通过持续状态（例如高血压）或急性诱导 诸如心肌梗塞（MI）之类的伤害。 MI的特征是冠状动脉血管阻塞 导致缺血。受缺血影响的心肌细胞（CMS）发生坏死和凋亡。清除 由此产生的细胞碎片，免疫细胞浸润该区域，而居民成纤维细胞开始分泌 细胞外基质的疤痕以保持心脏的结构完整性。这种雄辩的反应是必不可少的 克服最初的伤害和夸大任何特定阶段可能会产生有害影响。而 与高血压和MI相关的疾病病因是独一无二的，它们具有相似的特征，例如 肥大，炎症和纤维化。为了更好地了解病理心脏重塑的过程， 我们进行了RNA测序以识别与病理相关的转录基因表达谱 命运。我们确定了一个富含脯氨酸的蛋白质（SPRR）的家族，这些蛋白质在疾病中受到差异调节。 SPRR1A在CFS和边界区的CMS（BZ）中的炎症细胞因子（BZ）高度上调 mi。初步数据表明SPRR1A与肿瘤坏死因子（TNF）之间的预测结合位点 受体相关因子（TRAF）2，一种E3泛素连接酶，对TNF受体作用于TNF受体 质膜传播炎症信号传导。进一步的调查使我们假设 SPRR1A正在改变CMS中的泛素化状态或蛋白酶体功能，以阻止促发炎信号传导 并允许发生炎症途径的增加。单独，sprr1a和traf2可能 还在沿损伤边界的细胞存活率中发挥作用。了解 MI之后的康复反应将建立进一步的治疗发展所需的基础。这个建议 旨在确定新型的体外作用机理和与体内并发症相关的相关性 SPRR1A表达的调制。