Role of Clec2d-DAMP interactions in the pathophysiology of tissue injury and sepsis

Clec2d-DAMP 相互作用在组织损伤和脓毒症病理生理学中的作用

• 批准号: 10164709
• 负责人: KENNETH L ROCK
• 金额: $ 48.09万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-20 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10164709
• 关键词: Adult Respiratory Distress Syndrome; Affect; Autoimmunity; Binding; C Type Lectin Receptors; C-Type Lectins; CXCR4 gene; Cells; Chromatin; Complex; DNA Binding; Data; Defense Mechanisms; Disease; Endotoxemia; Functional disorder; Goals; Grant; HMGB1 gene; Histones; Immune; Immune system; Immunologic Receptors; Infarction; Inflammation; Inflammatory; Injury; Kidney; Lead; Ligands; Literature; Liver; Macrophage-1 Antigen; Mediating; Molecular; Molecular Target; Morbidity - disease rate; Mucins; Mutation; Nitric Oxide; Nucleosomes; Organ; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pattern; Pharmaceutical Preparations; Play; Post-Translational Protein Processing; Protein Region; Reperfusion Injury; Role; Sepsis; Signal Transduction; Specificity; Sterility; Stroke; Syndrome; T-Lymphocyte; Testing; Toll-like receptors; Trauma; base; cancer cell; cell injury; cytokine; extracellular; histone modification; in vivo; insight; macrophage; mortality; pathogen; prevent; receptor; response; response to injury; therapeutic target; tissue injury

Abstract: The overall goal of this grant is to elucidate the specificity, function and role in disease pathogenesis of an innate immune receptor (CLEC2d) that we have discovered recognizes cellular histones and HMGB1. The importance of this project is that histones and HMGB1, when released from injured cells, at as damage- associated molecular patterns (DAMPS) that have been implicated in the pathogenesis of a number of important diseases, including sepsis, ischemia-reperfusion injury, toxic organ damage and autoimmunity. The study of CLEC2d will provide insight into how these DAMPs mediate their effects and whether CLEC2d could be a therapeutic target to block the contribution of these DAMPs to disease. The first aim will elucidate the function of CLEC2d in innate immune cells. We will explore the hypotheses that this CLEC is important for: (a) the direct stimulation of innate immune cells by histones and HMGB1; (2) stimulation of innate immune cells by histoneHMGB1-associated immunostimulatory molecules (PAMPs and DAMPs), and/or (3) the clearance of extracellular histones/HMGB1. The second aim will elucidate the role of the CLEC2d in histone/HMGB1- mediated diseases in vivo. We will explore the hypothesis that the CLECs are needed for histone/HMGB1- mediated pathology in vivo and the pathogenic sequelae of tissue injury and sepsis. The third aim will define the specificity of CLEC2d, how histone modifications alter recognition and responses, and whether this receptor recognizes other poly-basic DAMPs. Our hypotheses are that CLEC2d recognized a poly-basic degenerate motif(s) that is shared between 5 histones, HMGB1 and some other DAMPs and is sensitive to alternations in post-translational modifications of these DAMPs that occur in some diseases.

抽象的： 该赠款的总体目标是阐明在疾病发病机理中的特异性，功能和作用 我们发现的先天免疫受体（CLEC2D）识别细胞组蛋白和HMGB1。这 该项目的重要性是组蛋白和HMGB1从受伤的细胞释放时，为损害 - 相关的分子模式（潮湿）与许多人的发病机理有关 重要的疾病，包括败血症，缺血 - 再灌注损伤，有毒器官损伤和自身免疫性。这 CLEC2D的研究将提供有关这些抑制作用如何介导其效果以及Clec2d如何能够提供的见解 成为阻止这些阻尼对疾病的贡献的治疗靶标。第一个目标将阐明 Clec2d在先天免疫细胞中的功能。我们将探讨该CLEC对：（a）很重要的假设 由组蛋白和HMGB1直接刺激先天免疫细胞； （2）通过 组酮HMGB1相关的免疫刺激性分子（PAMP和潮湿）和/或（3）清除 细胞外组蛋白/HMGB1。第二个目标将阐明Clec2d在组蛋白/HMGB1-- 体内介导的疾病。我们将探讨以下假设：组蛋白/HMGB1-需要CALEC。 体内介导的病理学以及组织损伤和败血症的致病性后遗症。第三个目标将定义 CLEC2D的特异性，组蛋白的修饰如何改变识别和反应，以及这是否是否 受体识别其他多基质潮湿。我们的假设是Clec2d识别出多基础 退化基序（S）在5个组蛋白，HMGB1和其他一些潮湿之间共享，对 在某些疾病中发生的这些潮湿的翻译后修饰的交替。