Targeting renal inflammatory pathways of SLE nephritis in mouse and man

针对小鼠和人类 SLE 肾炎的肾脏炎症通路

• 批准号: 7770235
• 负责人: Anne Davidson
• 金额: $ 64.96万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-13 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7770235
• 关键词: Arts; Biological Assay; Biological Markers; Biopsy; Bromodeoxyuridine; Candidate Disease Gene; Cause of Death; Cell Separation; Cell physiology; Cells; Clinical; Collaborations; Complement Activation; Data; Data Set; Dendritic Cells; Dendritic cell activation; Development; Diagnosis; Disease; Disease remission; Endothelial Cells; Endothelium; Flow Cytometry; Gene Expression; Gene Expression Profiling; Genes; Genomics; Glomerulonephritis; Goals; Growth Factor; Histocytochemistry; Human; Hypertension; Hypoxia; ITGAM gene; Immunohistochemistry; Infiltration; Inflammation; Inflammatory; Kidney; Kidney Diseases; Label; Laboratories; Latex Bead; Link; Lupus; Messenger RNA; Microarray Analysis; Minor; Modeling; Mononuclear; Mus; Nephritis; Online Systems; Onset of illness; Outcome; Pathway interactions; Patients; Pattern; Phagocytes; Phenotype; Physiological; Population; Production; Prognostic Marker; Proteinuria; Relapse; Remission Induction; Reporting; Research Personnel; Risk; Sampling; Severities; Signal Transduction; Staging; Surface; System; Systemic Lupus Erythematosus; Testing; Therapeutic; Therapeutic Intervention; Time; Tissue Procurements; Toxic effect; Up-Regulation; Urine; base; chemokine; cytokine; disability; gene discovery; macrophage; man; molecular marker; monocyte; mouse model; novel; novel therapeutics; outcome forecast; peripheral blood; public health relevance; research study; response; tool; uptake; urinary

DESCRIPTION (provided by applicant): This proposal is a collaborative venture from the Davidson and Kretzler laboratories that reflects a set of converging experiments based on gene discovery in human and murine SLE nephritis, and a set of functional studies in mice based on hypotheses generated as a result of these studies. The proposal is based on the central hypothesis that molecular markers of SLE nephritis progression pathways can serve as predictors of outcome and therapeutic response. Using a unique model of remission induction of murine SLE nephritis we have identified two main physiologic pathways are associated disease onset and remission. These are: 1) activation of the renal endothelium and 2) activation of renal macrophages and dendritic cells with production of pro-inflammatory cytokines. Part of the signature is shared with other progressive murine renal diseases and both signatures overlap significantly with those found in human SLE renal biopsies. We have further discovered that activation of resident renal macrophages is a hallmark of onset of clinical nephritis in several disparate murine SLE models and is associated with upregulation of ITGAM, a gene that has recently been found to confer SLE risk. The current proposal focuses on the activation pathways of macrophages/dendritic cells in the kidneys with a view to identifying key pathways that could be targeted therapeutically. We will first determine the phenotype and origins of activated macrophages/monocytes in murine lupus kidneys and whether their precursors can be found in the peripheral blood. We will then characterize the function of activated macrophages and dendritic cells in the kidneys and urine sediment. We will use a combination of immuno- histochemistry, flow cytometry, functional studies and gene expression profiling to identify genes that are putative severity/prognostic markers or that are biomarkers for disease onset, remission and relapse. Parallel studies in human SLE renal biopsies and urinary cell pellets will allow us to identify pathways that can further be explored functionally in the murine models. At the same time candidate genes identified in the murine models will be evaluated in the human samples using a costume array qRT-PCR approach. More sophisticated systems based analysis of the human and murine data sets will help identify key signal transduction and transcriptional pathways that can be targeted therapeutically. Our studies allow us to make maximal use of large data sets to hone in on pathways that are likely to be shared among SLE patients. In addition we plan to build our consortium for standardized state-of-the-art tissue procurement and banking and to make data available through sophisticated web based tools for sharing with other investigators. PUBLIC HEALTH RELEVANCE: Kidney disease is a significant cause of death and disability in patients with SLE. Current treatments have insufficient efficacy and high toxicity. Because SLE patients differ from each other with respect to the patterns of kidney disease we will use several mouse models of SLE nephritis to understand more about the mechanisms for kidney inflammation and remission in different types of kidney disease and use the data obtained to probe information obtained from human SLE kidney biopsies. We will perform gene discovery experiments to identify novel patterns of gene expression that are associated with the various stages of kidney disease and with responses to treatment. Our studies should help us identify new pathogenetic disease mechanisms, to find novel targets for therapeutic intervention and to identify robust biomarkers that will help predict outcomes and responses to therapy.

描述（由申请人提供）：该提案是Davidson和Kretzler实验室的合作项目，反映了一组基于人类和小鼠SLE肾炎基因发现的融合实验，以及一组基于这些研究结果产生的假设的小鼠功能研究。该建议基于中心假设，即SLE肾炎进展途径的分子标志物可以作为结果和治疗反应的预测因子。使用一种独特的小鼠SLE肾炎缓解诱导模型，我们已经确定了两个主要的生理途径是相关的疾病发作和缓解。这些措施包括：1）激活肾内皮和2）激活肾巨噬细胞和树突细胞，产生促炎细胞因子。部分特征与其他进行性鼠肾脏疾病共享，并且两个特征与人SLE肾活检中发现的特征显著重叠。我们进一步发现，在几种不同的小鼠SLE模型中，常驻肾巨噬细胞的活化是临床肾炎发作的标志，并且与ITGAM（最近发现赋予SLE风险的基因）的上调相关。 目前的建议侧重于肾脏中巨噬细胞/树突状细胞的激活途径，以确定可以治疗的关键途径。我们将首先确定小鼠狼疮肾中活化的巨噬细胞/单核细胞的表型和起源，以及它们的前体细胞是否可以在外周血中找到。然后，我们将表征肾脏和尿沉渣中活化的巨噬细胞和树突状细胞的功能。我们将使用免疫组织化学、流式细胞术、功能研究和基因表达谱的组合来鉴定推定的严重程度/预后标志物或疾病发作、缓解和复发的生物标志物的基因。在人类SLE肾活检和尿细胞团中的平行研究将使我们能够确定可以在小鼠模型中进一步功能性探索的途径。同时，将使用服装阵列qRT-PCR方法在人样品中评价在鼠模型中鉴定的候选基因。基于人类和小鼠数据集的更复杂的系统分析将有助于确定可以治疗靶向的关键信号转导和转录途径。我们的研究使我们能够最大限度地利用大型数据集来研究SLE患者可能共享的途径。此外，我们计划建立我们的联盟，用于标准化的最先进的组织采购和银行，并通过复杂的基于网络的工具与其他研究者共享数据。 公共卫生关系： 肾脏疾病是SLE患者死亡和残疾的重要原因。目前的治疗方法疗效不足，毒性高。由于SLE患者在肾脏疾病模式方面彼此不同，我们将使用几种SLE肾炎小鼠模型来了解更多关于不同类型肾脏疾病的肾脏炎症和缓解机制，并使用所获得的数据来探测从人类SLE肾脏活检获得的信息。我们将进行基因发现实验，以确定与肾脏疾病的各个阶段和对治疗的反应相关的基因表达的新模式。我们的研究应该帮助我们确定新的致病机制，找到新的治疗干预目标，并确定强大的生物标志物，这将有助于预测结果和治疗反应。