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： 该资助的总体目标是阐明疾病发病机制中的特异性、功能和作用 我们发现的先天免疫受体（CLEC2d）可识别细胞组蛋白和 HMGB1。这 这个项目的重要性在于组蛋白和 HMGB1，当从受伤的细胞中释放时，会造成损伤- 相关分子模式（DAMPS）与许多疾病的发病机制有关 重要疾病，包括败血症、缺血再灌注损伤、中毒性器官损伤和自身免疫。这 对 CLEC2d 的研究将深入了解这些 DAMP 如何介导其作用以及 CLEC2d 是否可以 成为阻止这些 DAMP 对疾病产生影响的治疗靶点。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 CLEC 的重要假设：(a) 组蛋白和 HMGB1 对先天免疫细胞的直接刺激； (2) 刺激先天免疫细胞 组蛋白HMGB1相关免疫刺激分子（PAMP和DAMP），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-中的作用 介导的体内疾病。我们将探讨组蛋白/HMGB1-需要 CLEC 的假设 介导的体内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，组蛋白修饰如何改变识别和反应，以及这是否 受体识别其他多碱性 DAMP。我们的假设是 CLEC2d 识别了多元基础 5 个组蛋白、HMGB1 和其他一些 DAMP 之间共有的简并基序，并且对 在某些疾病中，这些 DAMP 的翻译后修饰会发生变化。