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（由申请人提供）：全身性红斑狼疮（SLE）是一种全身性自身免疫性疾病，具有未知的疗法生成和多器官参与，其特征是诱导组织损伤的自身抗体。树突状细胞（DC）是免疫系统的前哨，从周围采样危险信号。它们产生促炎性细胞因子，并与持续性免疫反应的继发性淋巴机器人中的天真T细胞相互作用，从而弥合先天和适应性免疫。我们最近表明，来自SLE 1,2,3狼疮的小鼠模型的髓样树突状细胞显示出早于疾病发作的I型Interferon特征。有趣的是，我们是从年轻的预先预测的狼疮prone prone sle 1,2,3小鼠的样品微阵列分析中发现的，与C57BL/6野生型相比，Kallikrein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验证。同样，基因组广泛的关联研究（GWAS）最近揭示了Kallikrein家族中的基因与SLE相关，这使得这是狼疮发病机理的重要靶标。到目前为止，还没有关于Kallikreins对DC的作用以及对免疫反应和狼疮自身免疫性的影响的系统研究。该项目的总体目标是分析Kallikrein-Kinin系统（KKS）在调节DC和其他免疫细胞中干扰素签名中的作用，并研究KKS对狼疮发病机理的影响，并为新的治疗靶标提供见解。自从他们发现一个世纪以前，丝氨酸肽酶家族的Kallikreins主要众所周知，在调节血压，氧化还原平衡，肾脏内纤维化，炎症和凋亡方面具有功能。直到最近几十年，文献才开始积累有关Kallikreins在免疫系统中作用的证据，尤其是Kallikrein-Kinin系统可以是一种危险信号，可以激活树突状细胞。在这种背景下，我旨在测试（1）假定候选者在Kallikrein-Kinin系统（KKS）中的影响，特别是对于树突状细胞和其他免疫子群中IFN信号和相关途径类型的影响（如果KKS的候选者可以改善卢普氏病）。