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Role of toll like receptors (TLRs)in Gd contrast agent induced skin fibrosis

Toll样受体(TLRs)在Gd造影剂诱导的皮肤纤维化中的作用

基本信息

批准号：
8549103
负责人：
SERGIO A JIMENEZ
金额：
$ 19.88万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-24 至 2014-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8549103
关键词：
Address Adenine Affect Animal Model Cell Surface Receptors Cells Chronic Kidney Failure Chronic Kidney Insufficiency Contrast Media Cytokine Activation Deposition Dermal Development Diet Disease Dose Event Exposure to Fibroblasts Fibrosis Gadolinium Gene Expression Histologic Human Human Characteristics Implant Infiltration Inflammation Infusion procedures Injection of therapeutic agent Investigation Kidney Kidney Diseases Kidney Failure Lesion Ligands Magnetic Resonance Modeling Molecular Molecular Target Mus Natural Immunity Nephrectomy Omniscan Pathogenesis Pathway interactions Patients Pattern Peripheral Blood Mononuclear Cell Process Production Publishing Pulmonary Fibrosis Pump Reporter Genes Reporting Rodent Role Scanning Scleroderma Signal Pathway Skin System Systemic Scleroderma TLR4 gene TLR7 gene Tail Testing Tissues Toll-Like Receptor Pathway Toll-like receptors Veins base chemokine cytokine effective therapy gadodiamide gadolinium oxide implantation interest macrophage monocyte novel research study response skin lesion therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Nephrogenic Systemic Fibrosis (NSF) is a rare condition occurring in a small subset of patients with renal insufficiency following exposure to Gadolinium based contrast agents (GdBCA). This disorder is characterized by severe dermal and systemic fibrosis with the presence of large numbers of activated macrophages, fibrocytes and fibroblasts in affected tissues. Several published studies have reported the development of skin lesions in sub-total nephrectomized rodents injected with high doses of GdBCA, however, these lesions do not demonstrate many of the histopathological characteristics of human NSF lesions. To overcome this flaw, we propose to develop a more realistic and informative animal model of NSF by utilizing mice with adenine-induced renal failure that have either been injected intravenously with high dose GdBCA or that have been exposed to GdBCA via subdermally implanted osmotic pumps or by intratracheal instillation. Given the intense interest in the role of macrophages and, in particular, of the Toll-like receptor (TLR) pathway in the development of fibrosis, we will perform extensive mechanistic studies to examine the role of macrophages and TLRs in the development of GdBCA induced fibrosis in this new model. The hypotheses to be tested will be: 1) GdBCA exposure induces NSF-like fibrotic lesions, 2) activated macrophages are required to induce these lesions; and 3) the induction requires engagement of TLR4 and/or TLR7. To test these hypotheses, the following specific aims are proposed: SPECIFIC AIM 1: Induce fibrosis by GdBCA administration in C57BL/6J mice with adenine induced renal failure. SPECIFIC AIM 2: Investigate the role of macrophages and of TLR4 and TLR7 in the development of fibrosis in mice with adenine induced renal disease. The studies proposed here will provide valuable information regarding the initial molecular events that couple exogenous or environmental etiologic factors with inflammation and fibrosis focusing on the participation of the innate immunity system and TLR responses in these processes. Furthermore, these studies will provide important clues regarding the pathogenesis of idiopathic systemic fibrotic disorders such as SSc and may allow the identification of novel potential therapeutic targets for these diseases.

描述（由申请人提供）：肾源性系统性纤维化（NSF）是一种罕见疾病，发生在一小部分肾功能不全患者暴露于钆基造影剂（GdBCA）后。这种疾病的特征是严重的真皮和全身纤维化，受影响的组织中存在大量活化的巨噬细胞、纤维细胞和成纤维细胞。几项已发表的研究报道了注射高剂量 GdBCA 的次全肾切除啮齿动物出现皮肤病变，然而，这些病变并未表现出人类 NSF 病变的许多组织病理学特征。为了克服这一缺陷，我们建议利用腺嘌呤诱导肾衰竭的小鼠开发一种更真实、信息更丰富的 NSF 动物模型，这些小鼠要么静脉注射高剂量 GdBCA，要么通过皮下植入渗透泵或通过气管内滴注暴露于 GdBCA。鉴于人们对这个角色的浓厚兴趣为了研究巨噬细胞，特别是 Toll 样受体 (TLR) 通路在纤维化发展中的作用，我们将进行广泛的机制研究，以检验巨噬细胞和 TLR 在这个新模型中 GdBCA 诱导的纤维化发展中的作用。要测试的假设是：1) GdBCA 暴露诱发 NSF 样纤维化病变，2) 需要激活的巨噬细胞来诱发这些病变； 3)诱导需要TLR4和/或TLR7的参与。为了检验这些假设，提出以下具体目标：具体目标 1：通过在患有腺嘌呤诱导的肾衰竭的 C57BL/6J 小鼠中施用 GdBCA 来诱导纤维化。具体目标 2：研究巨噬细胞以及 TLR4 和 TLR7 在腺嘌呤诱导的肾病小鼠纤维化发展中的作用。这里提出的研究将提供有关将外源或环境病因与炎症和纤维化耦合的初始分子事件的有价值的信息，重点关注炎症和纤维化的参与先天免疫系统和 TLR 在这些过程中的反应。此外，这些研究将为特发性系统性纤维化疾病（如 SSc）的发病机制提供重要线索，并可能为这些疾病确定新的潜在治疗靶点。