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.

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