Novel histone-binding C-type lectin receptors and their role in sterile inflammation and tissue injury

新型组蛋白结合 C 型凝集素受体及其在无菌炎症和组织损伤中的作用

基本信息

批准号：
10566947
负责人：
KENNETH L ROCK
金额：
$ 59.39万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-11-09 至 2027-10-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10566947
关键词：
Applications Grants Automobile Driving Binding Biological Biology C Type Lectin Receptors Cell Death Cells Communicable Diseases DNA Disease Endosomes Goals Health Histones Homologous Gene Host Defense Human Immune Immune system Infarction Inflammation Inflammatory Response Injury Innate Immune Response Ischemia Kidney Ligands Literature Liver Malignant Neoplasms Mediating Molecular Molecular Target Morbidity - disease rate Mus Myocardial Infarction Nature Nucleosomes Organ Pathogenesis Pathogenicity Pathologic Pathology Pattern Pharmaceutical Preparations Play Process Receptor Signaling Reperfusion Injury Reperfusion Therapy Role Sepsis Specificity Sterility Stroke Testing Tissues Toll-like receptors Translating Trauma Work cell injury extracellular in vivo insight mortality neutrophil novel prevent receptor receptor binding receptor function response tissue injury

项目摘要

Abstract The immune system has evolved mechanisms to recognize cell injury and in response stimulate sterile inflammation. This response contributes in important ways to both heath and disease. In this process, dying cells release Damage Associated Cell Patterns (DAMPs) that are detected by receptors on immune cells, which then trigger sterile inflammation. Histones are DAMPs that are major drivers of sterile inflammation and there is a recent growing literature implicating the release of and response to histones in the morbidity and mortality from tissue injury. Given the role of these DAMPs in the pathogenesis of disease, it is important to understand the receptors that engage these ligands and mediate their effects. Before our work, such receptors were unknown. We discovered the first cellular receptor for histones, which was the C-type lectin receptor (CLR/Clec) Clec2d. We showed that Clec2d plays an important role in innate immune responses to histones and the pathogenesis of disease in vivo. Our studies also revealed that Clec2d is not the whole story and that there must be another histone receptor(s) in mice that contributes to responses and disease. Moreover, human innate immune cells are similarly stimulated by histones, however when we went to translate our findings to humans, we found that the human homolog of Clec2d does not recognize histones. Therefore, there are as yet to be identified human histone receptors. Importantly, we have now discovered such novel Clec-histone receptors (CHRs) in both mice and humans and these discoveries form the basis for this grant application. We have two Aims: Aim 1 will elucidate the role of CHRs in innate immune responses to histones in vivo. We will define what innate immune cells use CHRs to sense histones in vivo, the nature of the subsequent responses, and their role in the sterile inflammatory response and pathogenic sequelae of tissue injury in vivo. The importance of this aim is that it will provide insight into disease pathogenesis and potentially identify new molecular targets for treating these conditions; and, Aim 2 will define the specificity, consequences and underlying mechanisms of histone stimulation of novel CHRs. The importance of this aim is that it will define the underlying mechanisms by which histones and their receptors trigger and regulate responses, which ultimately drive host defense and pathobiology.

抽象的免疫系统具有进化的机制来识别细胞损伤，并以反应刺激无菌性炎。这种反应以重要的方式对荒地和疾病做出了贡献。在此过程中，垂死的细胞释放损伤相关的细胞模式（潮湿），由免疫细胞上的受体检测到，然后触发无菌炎症。组蛋白是潮湿是无菌炎症的主要驱动因素，并且有一个最近不断增长的文献暗示了从组织损伤。鉴于这些潮湿在疾病的发病机理中的作用，了解接合这些配体并介导其作用的受体。在我们工作之前，此类受体是未知的。我们发现了组蛋白的第一个细胞受体，该受体是C型凝集素受体（CLR/CLEC）CLEC2D。我们表明，clec2d在对组蛋白的先天免疫反应和发病机理中起重要作用。体内疾病。我们的研究还表明，clec2d并不是整个故事，一定有另一个小鼠的组蛋白受体有助于反应和疾病。此外，人类先天免疫细胞类似地被组蛋白刺激，但是当我们将发现转化为人类时，我们发现人类Clec2d的同源物不识别组蛋白。因此，还可以识别组蛋白受体。重要的是，我们现在发现了两只小鼠的新型Clec-Histone受体（CHRS）人类和这些发现构成了此赠款应用的基础。我们有两个目标：目标1将阐明了CHR在体内对组蛋白的先天免疫反应中的作用。我们将定义什么先天免疫细胞使用CHRS在体内感知组蛋白，后续反应的性质及其在无菌中的作用体内组织损伤的炎症反应和致病性后遗症。这个目标的重要性是它将提供有关疾病发病机理的见解，并有可能识别用于治疗这些靶标的新分子靶标状况;并且，AIM 2将定义组蛋白的特异性，后果和潜在机制刺激新型CHR。此目标的重要性是它将定义的基本机制组蛋白及其受体触发并调节反应，最终推动宿主防御和病理生物学。