Mechanisms of Complement Dependent Immune Complex-Mediated Glomerulonephritis

项目总结 肾脏是一种人体拳头大小的免疫活性器官(体重的0.5%)。然而，20%-25%的 心输出量遍及肾脏，使其容易受到损伤和肾功能的丧失。在肾脏疾病中， 补体(C)激活和巨噬细胞(M？)渗透是发生的两个关键事件。两个方面都可以 是有益的还是有害的，根据微环境的不同，在不同的位置表现不同。 补体信号将M？导向炎症部位，并参与局部M？放大 其数量与肾功能呈负相关。虽然M？和C是交织在一起的，但我们只是 开始了解炎症的这两个方面是如何相互作用的。深入了解这些机制，请访问 在补体对贩运和M？极化的调节中发挥作用将为识别 没有有效治疗方法的肾脏疾病的新疗法。随着先进技术的出现 和更好的疾病模型，我们开始在更好地理解肾小球、M？和 补充生物学和疾病期间发生的变化。这里提出的工作的目标是 用FH依赖免疫复合体介导的肾小球肾炎了解肾小球炎症 (ICGN)模型。我们的初步研究表明，Mä和T的招聘人数显著增加 淋巴细胞穿过肾小球滤过屏障，导致慢性炎症，导致纤维化和 FH依赖型ICGN中的功能性肾功能衰竭。根据我们的结果，我们的假设是 补体受体导致M？前体向肾脏募集，肾脏M？改变。 在那里它们会加重疾病的病理。为了检验这一假设，我们将(A)确定M？在FH中的作用 依赖的ICGN，(B)确定补体相关信号对FH依赖的ICGN中M？的影响， 以及(C)确定补体、Mo/M？和肾小球/内皮屏障(GEB)在FH依赖中的作用 ICGN.我们的FH依赖ICGN和GEB培养模型是独一无二的，具有以下实验特征 无与伦比。因此，我们使用这些模型的研究可以为疾病的机制提供相当大的洞察力 与人类相关的。我们处于有利地位，可以执行拟议的工作，拥有所有必要的和 研究这些细胞和途径的创新模型(体内和体外)和经过验证的技术(例如 分子成像、骨髓移植、遗传模型和18色流式细胞仪分析)。我们还有 组建了一支由巨噬细胞生物学、血管生物学、成像和白细胞贩运专家组成的团队，以 完成我们的目标。

PROJECT SUMMARY The kidney is an immunologically active organ the size of a human fist (0.5% body weight). Yet 20‐25 % of cardiac output traverses the kidney rendering it vulnerable to injury and loss of renal function. In renal diseases, complement (C) activation and macrophage (MØ) infiltration are two crucial events that occur. Both facets can be beneficial or detrimental, and behave differently at different locations depending on the microenvironment. Complement signaling directs MØ to sites of inflammation and participates in local MØ amplification, the numbers of which correlate negatively with renal function. Although MØ and C are intertwined, we are only beginning to understand how these two facets of inflammation interact. Gaining insight into the mechanisms at play in the regulation of trafficking and polarization of MØ by complement will open avenues for identification of novel therapeutics for kidney diseases that have no effective therapies. With the advent of advanced technology and better disease models, we are beginning to make inroads into better understanding glomerular, MØ and complement biology and the changes that occur during disease. The goal of the work proposed here is to understand glomerular inflammation using FH dependent immune complex mediated glomerulonephritis (ICGN) model. Our preliminary studies show that there is significant increase in recruitment of MØ and T lymphocytes across the glomerular filtration barrier, resulting in chronic inflammation that leads to fibrosis and functional renal failure in FH dependent ICGN. Based on our results, our hypothesis is that signaling through complement receptors leads to recruitment of MØ precursors to the kidney and alteration of MØ in the kidney, where they aggravate disease pathology. To test this hypothesis, we will (a) determine the role of MØ in FH dependent ICGN, (b) determine the impact of complement associated signaling on MØ in FH-dependent ICGN, and (c) determine the role of complement, Mo/MØ and glomerular/endothelial barrier (GEB) in FH-dependent ICGN. Our model of FH-dependent ICGN and GEB in culture are unique, with experimental features that are unrivaled. Thus, our studies using these models can provide considerable insights into mechanisms of disease relevant to human beings. We are well positioned to perform the proposed work, having all the necessary and innovative models (in vivo and in vitro) and validated technologies to interrogate these cells and pathways (e.g. molecular imaging, bone marrow transplants, genetic models and 18-color FACS analysis). We have also assembled a team of experts in macrophage biology, vascular biology, imaging and leukocyte trafficking, to accomplish our goals.