Endothelia mechanisms of leukocyte accumulation in glomerulonephritis

肾小球肾炎白细胞积聚的内皮机制

基本信息

批准号：
7903751
负责人：
Tanya N Mayadas
金额：
$ 4.79万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-21 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7903751
关键词：
Abbreviations Actins Address Adhesions Affect Animal Model Animals Antibodies Antigen-Antibody Complex Binding Biological Biological Assay Cells Complement Data Deposition Development Disease Endothelial Cells Endothelium Family Gene Expression Profile Glomerular Capillary Glomerulonephritis Guanine Guanine Nucleotide Exchange Factors Guanosine Triphosphate Phosphohydrolases Human Immune Immune response In Vitro Inflammation Inflammatory Injury Intercellular adhesion molecule 1 Kidney Kidney Diseases Knock-in Mouse Knockout Mice Leukocyte Rolling Leukocyte Trafficking Leukocytes Ligands Link Mediating Mitogen-Activated Protein Kinases Modeling Molecular Monomeric GTP-Binding Proteins Mus Nephritis Nephrotoxic Partner in relationship Physiological Play Receptor Signaling Regulation Relative (related person)Renal function Research Personnel Role Signal Pathway Signal Transduction T-Lymphocyte TNF gene TNFRSF1A gene TNFRSF1B gene Testing Transgenic Animals Transgenic Mice Tumor Necrosis Factor Receptor Umbilical vein Vascular Cell Adhesion Molecule-1 adhesion receptor base cell type cremaster muscle cytokine glomerular basement membrane glomerular endothelium human MAPK14 protein in vivo Model inorganic phosphate intravital microscopy member migration monolayer mouse model novel therapeutics postcapillary venule programs recombinase rho GTP-Binding Proteins therapeutic target treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Leukocyte accumulation is the hallmark of inflammatory renal diseases. TNF, a potent cytokine that regulates leukocyte trafficking, is essential for the development of glomerulonephritis (GN) in animal models. The biological activities of TNF are mediated by two functionally distinct TNFRs, TNFR1 and TNFR2. We have shown that TNFR2 is critical for GN. TNFR2 deficient mice were completely protected from antibody- mediated nephrotoxic nephritis that was associated with decreased renal leukocyte accumulation and glomerular complement deposition. Furthermore, TNFR2 on intrinsic parenchymal cells but not circulating leukocytes was essential for GN. Notably, TNFR2 was induced on glomerular endothelium of nephritic kidneys. In contrast, a deficiency in TNFR1 resulted in an enhanced immune response and renal T cell accumulation resulting in GN. Thus TNFRs play differential roles in GN. The major objective of this proposal is to identify the intrinsic cell type and mechanisms responsible for TNFR2 dependent leukocyte accumulation and glomerular damage. Aim I will address the hypothesis that TNFR2 engagement on endothelial cells induces a transcriptional program required for leukocyte recruitment and subsequent glomerular injury. The endothelial adhesion receptor dependent signaling mechanisms required for leukocyte transmigration remain enigmatic. Our preliminary data demonstrates that TNF-induced leukocyte transmigration is dependent on DOCK4, a recently identified member of the COM family of guanine exchange factors for small GTPases that we show is highly expressed on cultured endothelial cells and glomerular endothelium. Aim II will test the hypothesis that endothelial adhesion receptor signaling to DOCK4 modulates leukocyte transmigration and glomerular damage. These aims will exploit a) established mouse models of antibody induced GN, and antibody and TNF-induced leukocyte recruitment that are amenable to intravital microscopy, b) transcriptional profiling of nephritic kidneys and in vitro leukocyte transmigration assays under physiological flow conditions, c) transgenic mice with inducible expression of TNFR2 only in the endothelium, and mice lacking DOCK4 specifically in the endothelial lineage. Completion of the aims will increase our understanding of endothelial dependent mechanisms of inflammation mediated glomerular injury that could aid in the development of new therapeutic strategies for the treatment of GN.

描述（由申请人提供）：白细胞积聚是炎症性肾病的标志。 TNF 是一种调节白细胞运输的强效细胞因子，对于动物模型中肾小球肾炎 (GN) 的发展至关重要。 TNF 的生物活性由两种功能不同的 TNFR（TNFR1 和 TNFR2）介导。我们已经证明 TNFR2 对于 GN 至关重要。 TNFR2缺陷小鼠完全免受抗体介导的肾毒性肾炎的影响，这种肾毒性肾炎与肾脏白细胞积累和肾小球补体沉积减少有关。此外，内在实质细胞而非循环白细胞上的 TNFR2 对于 GN 至关重要。值得注意的是，TNFR2 在肾病肾的肾小球内皮上被诱导。相反，TNFR1 缺陷会导致免疫反应增强和肾 T 细胞积聚，从而导致肾小球肾炎。因此 TNFR 在 GN 中发挥着不同的作用。该提案的主要目标是确定导致 TNFR2 依赖性白细胞积累和肾小球损伤的内在细胞类型和机制。目的我将提出以下假设：TNFR2 与内皮细胞的结合会诱导白细胞募集和随后的肾小球损伤所需的转录程序。白细胞迁移所需的内皮粘附受体依赖性信号传导机制仍然是个谜。我们的初步数据表明，TNF 诱导的白细胞迁移依赖于 DOCK4，DOCK4 是最近发现的小 GTP 酶鸟嘌呤交换因子 COM 家族的成员，我们发现 DOCK4 在培养的内皮细胞和肾小球内皮细胞上高度表达。目标 II 将检验以下假设：内皮粘附受体向 DOCK4 发出信号，调节白细胞迁移和肾小球损伤。这些目标将利用 a) 已建立的抗体诱导的 GN 小鼠模型，以及抗体和 TNF 诱导的白细胞募集，这些模型适合活体显微镜检查，b) 肾病肾的转录谱和生理流条件下的体外白细胞迁移测定，c) 转基因仅在内皮细胞中诱导表达 TNFR2 的小鼠，以及在内皮细胞谱系中特异性缺乏 DOCK4 的小鼠。完成这些目标将增加我们对炎症介导的肾小球损伤的内皮依赖性机制的理解，这可能有助于开发治疗肾小球肾炎的新治疗策略。