Mechanisms of Complement Dependent Immune Complex-Mediated Glomerulonephritis

补体依赖性免疫复合物介导的肾小球肾炎的机制

• 批准号: 9766281
• 负责人: Jessy J Alexander
• 金额: $ 23.77万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-17 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9766281
• 关键词: AP20187; Address; Affect; Antigen-Antibody Complex; Biology; Blood Circulation; Blood Platelets; Blood Vessels; Body Weight; Bone Marrow; Bone Marrow Transplantation; Breeding; C3AR1 gene; C3bi; CD4 Positive T Lymphocytes; Cardiac Output; Cell Culture Techniques; Cells; Chemotactic Factors; Chronic; Chronic Kidney Failure; Clinical; Color; Complement; Complement 3a; Complement 5a; Complement Activation; Complement Factor H; Complement Receptor; Consumption; Development; Disease; Disease model; Endothelial Cells; Endothelium; Event; Extravasation; Fibrosis; Generations; Genetic Models; Glomerular Filtration Rate; Glomerulonephritis; Goals; Human; Image; Immunologics; In Situ; In Vitro; Infection; Infiltration; Inflammation; Inflammatory; Injury; Kidney; Kidney Diseases; Kidney Failure; Leukocyte Trafficking; Link; Location; Longevity; Mediating; Metabolic; Modeling; Mus; Organ Size; Pathology; Pathway interactions; Phenotype; Play; Population; Positioning Attribute; Process; Public Health; Regulation; Renal function; Role; Serum Sickness; Severity of illness; Signal Transduction; Site; Study models; System; T-Lymphocyte; Technology; Testing; Therapeutic; Tissues; Wild Type Mouse; Woman; Work; activation product; base; complement system; cytokine; effective therapy; glomerular endothelium; glomerular filtration; immune clearance; improved; in vitro Model; in vivo; innovation; insight; intravital microscopy; kidney dysfunction; macrophage; men; molecular imaging; monocyte; mortality; novel; novel therapeutics; phenotypic biomarker; podocyte; prevent; recruit; response; trafficking

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.

项目概要 肾脏是一个免疫活性器官，大小相当于人类拳头（体重的 0.5%）。然而 20‐25% 心输出量穿过肾脏，使其容易受伤和肾功能丧失。在肾脏疾病中， 补体 (C) 激活和巨噬细胞 (MØ) 浸润是发生的两个关键事件。两面都可以 有利或有害，并且根据微环境在不同位置表现不同。 补体信号传导将 MØ 引导至炎症部位并参与局部 MØ 放大， 其数量与肾功能呈负相关。尽管MØ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如何相互作用。深入了解其中的机制 补体在贩运调节和 MØ 两极分化中的作用将为识别 针对尚无有效疗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，我们开始更好地了解肾小球、MØ 和 补充生物学和疾病期间发生的变化。这里提出的工作目标是 使用 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，MØ 和 T 的招募显着增加 淋巴细胞穿过肾小球滤过屏障，导致慢性炎症，从而导致纤维化和 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，信号通过 补体受体导致 MØ 前体募集到肾脏并改变肾脏中的 MØ， 它们会加剧疾病病理。为了检验这一假设，我们将 (a) 确定 MØ 在 FH 中的作用 (b) 确定 FH 依赖性 ICGN 中补体相关信号传导对 MØ 的影响， (c) 确定补体、Mo/MØ 和肾小球/内皮屏障 (GEB) 在 FH 依赖性中的作用 ICGN。我们的 FH 依赖性 ICGN 和 GEB 培养模型是独特的，其实验特征是 无与伦比的。因此，我们使用这些模型的研究可以为疾病机制提供相当多的见解 与人类相关。我们完全有能力执行拟议的工作，拥有所有必要的和 创新模型（体内和体外）和经过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、成像和白细胞运输领域的专家组成的团队， 实现我们的目标。