Endothelia mechanisms of leukocyte accumulation in glomerulonephritis

肾小球肾炎白细胞积聚的内皮机制

• 批准号: 7322748
• 负责人: Tanya N Mayadas
• 金额: $ 34.65万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-07 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7322748
• 关键词: Abbreviations; Actins; Address; Adhesions; Affect; Animal Model; Animals; Antibodies; Antigen-Antibody Complex; Binding; Biological; Biological Assay; Cells; Complement; Condition; 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

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（由申请方提供）：白细胞蓄积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，在动物模型中对肾小球肾炎（GN）的发展至关重要。TNF的生物活性由两种功能不同的TNFR，TNFR 1和TNFR 2介导。我们已经证明TNFR2对GN至关重要。TNFR2缺陷小鼠完全免于抗体介导的肾毒性肾炎，其与肾白细胞积聚和肾小球补体沉积减少相关。此外，固有实质细胞上的TNFR2而不是循环白细胞是GN所必需的。值得注意的是，TNFR2在肾炎肾的肾小球内皮上被诱导。相比之下，TNFR1的缺乏导致增强的免疫应答和肾T细胞积聚，从而导致GN。因此，TNFR在GN中发挥不同的作用。本提案的主要目的是鉴定负责TNFR2依赖性白细胞积聚和肾小球损伤的内在细胞类型和机制。目的：我将阐述TNFR2在内皮细胞上的参与诱导白细胞募集和随后的肾小球损伤所需的转录程序的假设。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，肿瘤坏死因子诱导的白细胞迁移是依赖于DOCK4，最近确定的小GTP酶的鸟嘌呤交换因子COM家族的成员，我们显示是高度表达的培养的内皮细胞和肾小球内皮细胞。目的II将检验内皮细胞粘附受体信号转导DOCK 4调节白细胞迁移和肾小球损伤的假设。这些目标将利用a）建立的抗体诱导的GN以及抗体和TNF诱导的白细胞募集的小鼠模型，其适合于活体显微镜检查，B）在生理流动条件下的肾炎肾的转录谱分析和体外白细胞迁移测定，c）仅在内皮中具有TNFR 2的诱导型表达的转基因小鼠，以及在内皮谱系中特异性缺乏DOCK 4的小鼠。这些目标的完成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GN的新治疗策略。