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

摘要： 这项资助的总体目标是阐明A型流感病毒的特异性、功能和在疾病发病机制中的作用。 我们发现的先天免疫受体(CLEC2d)识别细胞组蛋白和HMGB1。这个 这个项目的重要性是，当组蛋白和HMGB1从损伤的细胞中释放出来时，就像损伤一样- 相关的分子模式(DAMP)与许多 重要疾病，包括脓毒症、缺血再灌注损伤、毒性器官损伤和自身免疫。这个 对CLEC2d的研究将深入了解这些阻尼剂如何调节其影响，以及CLEC2d是否可能 作为治疗的靶点，阻止这些湿气对疾病的贡献。第一个目标将阐明 CLEC2d在先天免疫细胞中的作用我们将探讨CLEC对以下方面的重要假设： 组蛋白和HMGB1对天然免疫细胞的直接刺激； 组蛋白HMGB1相关的免疫刺激分子(PAMPs和DAMPS)，和/或(3)清除 细胞外组蛋白/HMGB1。第二个目的是阐明CLEC2d在组蛋白/HMGB1中的作用。 体内介导性疾病。我们将探索组蛋白/HMGB1-需要CLECs的假设。 介导体内病理和组织损伤和败血症的致病后遗症。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 受体识别其他多碱基的湿气。我们的假设是CLEC2d识别出一种多碱基 5个组蛋白、HMGB1和其他一些阻尼剂共有的简并基序(S)，对 某些疾病中出现的这些阻滞剂的翻译后修饰的变化。

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.