A critical role of TAM receptors in autoimmune nephritis

TAM 受体在自身免疫性肾炎中的关键作用

基本信息

批准号：
9195086
负责人：
Wen-Hai Shao
金额：
$ 12.93万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-12-01 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9195086
关键词：
Acute Animal Model Anti-Glomerular Basement Membrane Disease Antibodies Apoptotic Attention Autoantibodies Autoimmune Diseases Autoimmune Process Autoimmunity Autologous Bone Marrow Cell Line Cell Proliferation Cells Cessation of life Chimera organism Chronic Clinical Data Development Disease Disease Progression Endothelial Cells Family Glomerular basement membrane antibody Glomerulonephritis Human Immune Immune Tolerance Immunofluorescence Immunologic Impairment In Vitro Infiltration Inflammation Inflammatory Inflammatory Response Injury Kidney Kidney Failure Knockout Mice Knowledge Leukocytes Ligands Light Lupus Lupus Nephritis Marrow Measures Mediating Membrane Modeling Molecular Mus Nephritis Nephrotoxic PTPRC gene Pathologic Pathology Pattern Phagocytosis Phase Physiological Play Production Proliferative Glomerulonephritis Receptor Protein-Tyrosine Kinases Reporting Role Serum Sheep Sister Source Survival Rate Syndrome Systemic Lupus Erythematosus Testing Therapeutic Intervention cell type chemokine cytokine experimental study glomerular basement membrane in vivo insight kidney cell macrophage mesangial cell monocyte mouse model nephrotoxicity public health relevance radioresistant receptor receptor function targeted treatment therapeutic target

项目摘要

DESCRIPTION (provided by applicant: Mer belongs to the TAM subfamily (Tyro-3, Axl, Mer) of receptor tyrosine kinases. Receptors of this family play an important role in apoptotic cell clearance and immune tolerance while performing homeostatic phagocytosis. Nephrotoxic serum (NTS)-induced experimental nephritis has been a useful model that produces pathological changes similar to those seen in immune-mediated glomerulonephritis. Using this model, we found an important protective role for Mer. We showed that Mer-KO mice developed severe early stage renal damage, which led to lower survival. In seeming contrast to these results, Axl was reported to promote mesangial cell proliferation in a similar model, and might hence worsen the disease. In this proposal, we will explore more deeply the physiological functions of both Mer and Axl in the development of experimental nephritis and spontaneous lupus nephritis. Using mice lacking Axl, Mer, or both receptors, we will follow disease development by enumerating apoptotic cells, and by quantitating cytokine/chemokine secretion and leukocyte infiltration and activation. The expression pattern of Mer will be further studied along with Axl in renal cells by FACS and immunofluorescence while following disease progress in those animal models. We will test our hypothesis that the absence of Mer and Axl leads to impaired apoptotic cell clearance and skewed pro-inflammatory cytokine/chemokine secretion and enhanced monocyte/macrophage infiltration in the kidney. Monocytes/macrophages and glomerular cells lacking TAM (Mer-KO, Axl- KO, or Mer/Axl-dKO) receptors are aberrantly activated and severe nephritis occurs. We will construct chimeric mice to ask if the renal damage is caused by resident renal cells or by migrated Mer/Axl- bearing cells. We will further investigate the role of TAM receptors on disease progress in lupus- prone B6/sle123 mice. Results from this study will extend our understanding of the mechanisms in which Mer and Axl regulate chronic inflammation and autoimmunity. Data may reveal potential therapeutic targets for lupus nephritis.

描述（由申请人提供：MER属于受体酪氨酸激酶的TAM亚科（Tyro-3，AXL，MER）。该家族的受体在凋亡细胞清除和免疫耐受性中起着重要作用，同时进行体内稳态吞噬作用。肾上腺素（NTS）诱导的肾小球症有用的模型，是一种有用的模型。免疫介导的肾小球肾脏炎，我们发现MER的重要保护作用。实验性肾炎和自发性狼疮性肾炎。 MER的表达模式将通过FACS和免疫荧光在肾细胞中进一步研究，同时在这些动物模型中疾病进展。我们将检验我们的假设，即缺乏MER和AXL会导致凋亡细胞清除受损，并偏向促炎性细胞因子/趋化因子分泌，并增强肾脏的单核细胞/巨噬细胞浸润。单核细胞/巨噬细胞和肾小球细胞缺乏TAM（Mer-KO，Axl-KO或Mer/Axl-DKO）受体被异常激活，并且发生严重的肾炎。我们将构建嵌合小鼠，询问肾脏损伤是由常驻肾细胞或迁移的Mer/Axl轴承细胞引起的。我们将进一步研究TAM受体在狼疮B6/SLE123小鼠中疾病进展的作用。这项研究的结果将扩展我们对MER和AXL调节慢性炎症和自身免疫性的机制的理解。数据可能揭示了狼疮肾炎的潜在治疗靶标。