Role of kallikreins in lupus

激肽释放酶在狼疮中的作用

• 批准号: 9121460
• 负责人: Uma Sriram
• 金额: $ 7.8万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9121460
• 关键词: Affect; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Antigen-Antibody Complex; Apoptosis; Autoantibodies; Autoimmunity; B-Lymphocytes; Bone Marrow; Bradykinin; C57BL/6 Mouse; Cell Aging; Cells; Chymosin; Clinical; Coagulation Process; Complement; Complex; Complication; Data; Deltastab; Dendritic Cells; Dendritic cell activation; Disease; Equilibrium; Family; Fibrosis; Flare; Gene Family; Genes; Goals; Gonadal Steroid Hormones; Health; Immune; Immune response; Immune system; In Vitro; Inbred MRL lpr Mice; Inflammation; Interferon Type I; Interferon-alpha; Interferons; Kallikrein-Kinin System; Kidney; Kidney Diseases; Kininogenase; Kinins; Lead; Literature; Lupus; Lupus Nephritis; Lymphoid; Metabolic; Metabolic Pathway; Microarray Analysis; Morbidity - disease rate; Mus; Myelogenous; Natural Immunity; Nephritis; Onset of illness; Organ; Outcome; Oxidation-Reduction; Pathogenesis; Pathway interactions; Patients; Peptide Hydrolases; Peptides; Pharmaceutical Preparations; Predisposition; Production; Renin; Role; SLEB3 gene; Sampling; Sentinel; Serine; Signal Transduction; Systemic Lupus Erythematosus; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Time; Tissue Kallikrein; Tissues; Validation; adaptive immunity; base; blood pressure regulation; cell age; cell type; complement pathway; congenic; cytokine; genome wide association study; human subject; in vivo; insight; lupus prone mice; macrophage; member; mortality; mouse model; neutrophil; new therapeutic target; novel; novel therapeutics; protective effect; research study; systemic autoimmune disease; targeted treatment

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is a systemic autoimmune disease, with unknown etiopathogenesis and multi-organ involvement, characterized by autoantibodies that induce tissue damage. Dendritic cells (DCs) are the sentinels of the immune system sampling danger signals from the periphery. They produce proinflammatory cytokines, and interact with naive T cells in secondary lymphoid organs evoking an appropriate immune response, thus bridging the innate and adaptive immunity. We have shown recently that myeloid dendritic cells from the Sle 1,2,3 lupus-prone mouse model, show a Type I Interferon Signature that predates disease onset. Interestingly, we have discovered from a sample microarray analysis of bone-marrow-derived dendritic cells (BMDCs) from young pre-diseased lupus-prone Sle 1,2,3 mouse that many members of the kallikrein family of genes show very low expression as compared to the C57BL/6 wild type; the results have been validated by real-time PCR as well. Also Genome Wide Association Studies (GWAS) have recently revealed that the genes in the kallikrein family are associated with SLE, making this an important target in lupus pathogenesis. So far there has been no systematic study on the role of kallikreins on DCs and the impact on immune response and lupus autoimmunity. The overall goal of this project is to analyze the role of kallikrein-kinin system (KKS) in regulating he Interferon Signature in DCs and other immune cells and to study the impact of the KKS on lupus pathogenesis and provide insights to new therapeutic targets. Since their discovery over a century ago, kallikreins, a family of serine peptidases, are majorly known to have functions in regulating blood pressure, redox balance, fibrosis within the kidneys, inflammation and apoptosis. It is only in the last couple of decades that literature is beginning to accumulate evidence on the role of kallikreins in the immune system, especially that the kallikrein-kinin system can be a danger signal that can activate dendritic cells. With this background I aim to test (1) the effects of putative candidates in kallikrein-kinin system (KKS), specifically on Type IFN signaling and related pathways in dendritic cells and other immune subsets (2) if candidates of the KKS can ameliorate lupus disease.

描述（申请人提供）：系统性红斑狼疮（SLE）是一种全身性自身免疫性疾病，其病因不明，多器官受累，其特征是自身抗体诱导组织损伤。树突状细胞（DC）是免疫系统从外周采集危险信号的哨兵。它们产生促炎细胞因子，并与次级淋巴器官中的幼稚 T 细胞相互作用，引发适当的免疫反应，从而架起先天免疫和适应性免疫的桥梁。我们最近发现，来自易患 Sle 1,2,3 狼疮的小鼠模型的骨髓树突状细胞显示出早于疾病发作的 I 型干扰素特征。有趣的是，我们从年轻的易患狼疮的 Sle 1,2,3 小鼠的骨髓源性树突状细胞 (BMDC) 样本微阵列分析中发现，与 C57BL/6 野生型相比，激肽释放酶基因家族的许多成员表现出非常低的表达；结果也通过实时 PCR 进行了验证。全基因组关联研究 (GWAS) 最近还表明激肽释放酶家族中的基因与 SLE 相关，使其成为狼疮发病机制的重要靶点。迄今为止，还没有关于激肽释放酶对DC的作用以及对免疫反应和狼疮自身免疫的影响的系统研究。该项目的总体目标是分析激肽释放酶-激肽系统（KKS）在调节树突状细胞和其他免疫细胞中干扰素特征中的作用，研究KKS对狼疮发病机制的影响，并为新的治疗靶点提供见解。自一个多世纪前发现以来，激肽释放酶（丝氨酸肽酶家族）主要具有调节血压、氧化还原平衡、肾脏纤维化、炎症和细胞凋亡的功能。直到最近几十年，文献才开始积累关于激肽释放酶在免疫系统中作用的证据，特别是激肽释放酶-激肽系统可能是激活树突状细胞的危险信号。在此背景下，我的目标是测试 (1) 激肽释放酶-激肽系统 (KKS) 中假定候选药物的影响，特别是对树突状细胞和其他免疫亚群中的 IFN 型信号传导和相关通路的影响 (2) KKS 候选药物是否可以改善狼疮疾病。