Mechanisms of Complement Dependent Immune Complex-Mediated Glomerulonephritis

项目摘要 肾脏是一个免疫活性器官，大小相当于人的拳头（体重的0.5%）。然而，20 - 25%的 心输出量穿过肾脏，使其易于损伤和丧失肾功能。在肾脏疾病中， 补体（C）活化和巨噬细胞（MPEG4）浸润是发生的两个关键事件。这两个方面都可以 有益或有害，并根据微环境在不同位置表现不同。 补体信号传导将MMP 3引导至炎症部位并参与局部MMP 3扩增， 其数量与肾功能呈负相关。虽然MPEG4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 通过补充，在管制贩运和毒品两极分化方面发挥作用，将为查明 用于尚无有效疗法的肾病的新疗法。随着先进技术的出现 和更好的疾病模型，我们开始更好地了解肾小球，肾小球和 补体生物学和疾病期间发生的变化。这里提出的工作目标是 用FH依赖性免疫复合物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，有显著增加招聘的MPEG4和T 淋巴细胞穿过肾小球滤过屏障，导致慢性炎症，导致纤维化， FH依赖性ICGN中的功能性肾衰竭。根据我们的结果，我们的假设是， 补体受体导致MclO前体向肾脏的募集和MclO在肾脏中的改变， 加重了疾病的病理。为了验证这一假设，我们将（a）确定MMPs在FH中的作用 （B）确定补体相关信号传导对FH依赖性ICGN中的MRF的影响， 和（c）确定补体、Mo/Mc和肾小球/内皮屏障（GEB）在FH依赖性免疫应答中的作用。 ICGN。我们培养的FH依赖性ICGN和GEB模型是独特的，具有以下实验特征： 无与伦比因此，我们的研究使用这些模型可以提供相当深入的了解疾病的机制 与人类有关。我们有能力执行拟议的工作，拥有所有必要的和 创新的模型（体内和体外）和经验证的技术来询问这些细胞和途径（例如， 分子成像、骨髓移植、遗传模型和18色FACS分析）。我们还 组建了一个巨噬细胞生物学、血管生物学、成像和白细胞运输方面的专家小组， 实现我们的目标。

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.