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C3aR and C5aR Modulate T-cell Responses in the MRL Mouse

C3aR 和 C5aR 调节 MRL 小鼠的 T 细胞反应

基本信息

批准号：
7570091
负责人：
MICHAEL C BRAUN
金额：
$ 28.97万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-01 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7570091
关键词：
Anaphylatoxins Animals Antibodies Antigen-Antibody Complex Antigen-Presenting Cells Apoptosis Autoimmunity B-Lymphocytes Back Biological Process Bone Marrow Transplantation C5a anaphylatoxin receptor CD3 Antigens CD4 Positive T Lymphocytes Cell Culture Techniques Cell physiology Cells Cessation of life Clinical Coculture Techniques Comparative Study Complement Complement 3a Complement 5a Complement Activation Complex Cytoskeleton Data Deposition Development Disease Environment G-Protein-Coupled Receptors Generations Genetic Helper-Inducer T-Lymphocyte Histology Human Immune Immune response Immunologics Immunophenotyping Inbred MRL lpr Mice Injury Kidney Kidney Diseases Kidney Failure Kidney Transplantation Laboratories Leucocytic infiltrate Leukocytes Lupus Lupus Nephritis Lymphocyte Lymphoid Lymphoid Tissue Measures Mediating Modeling Mus PTPRC gene Pathogenesis Patients Pattern Population Production Proteinuria Receptor Inhibition Relative (related person)Research Design Research Personnel Research Proposals Role Severities Severity of illness Signal Transduction Splenocyte Study of serum Survival Analysis System Systemic Lupus Erythematosus T-Lymphocyte Tissues Transcriptional Regulation Vascular Permeabilities Work activation product attenuation base chemokine receptor cytokine genetic linkage granulocyte human disease kidney cell mouse model programs receptor receptor expression research study response

项目摘要

Systemic Lupus Erythematosus (SLE) is a heterogeneous disorder characterized by autoimmunity and the development of progressive immune complex renal disease. The pathogenesis of SLE is complex and multi- factorial; substantial clinical and experimental data supports roles for auto-antibodies, immune complexes, apoptosis, and effector T-cells in the development of SLE. Disturbances in the complement system are strongly associated with the development and progression of many forms of SLE particularily lupus nephrits. Complement activation results in the production of anaphylatoxins, C3a and C5a, which signal through ubiquitiously expressed G-protein coupled receptors (C3aR and C5aR). Signaling via the C3aR and C5aR have historically thought to function to active innate immune responses. The studies contained in this proposal are desinged to define and characterize the ability of C3aR and C5aR to alter adaptive immune responses in a biologically relevant complement depedent model of human disease, namely the MRL/lpr mouse model of lupus nephritis. Mice with targeted deletions of C3aR and C5aR as well as mice deficient in both the C3aR and the C5aR have been back-crossed 9 generations on to the MRL/lpr genetic background. Comparative studies of renal injury and immunologic responses including antigent presenting cell function, T-cell, and B-cell function will be performed. Additionally, experiments investigating renal parenchymal reponses in terms of cellualr proliferation, extra-cellular matrix production, and apoptosis will be performed. These studies are designed to advance our understanding of the mechanisms by which complement activation products modulate cellular immune responses and renal parenchymal responses in immune mediated renal injury.

系统性红斑狼疮（SLE）是一种异质性疾病，其特征在于自身免疫性，进行性免疫复合物肾病的发展。SLE的发病机制复杂多样，因子;大量的临床和实验数据支持自身抗体，免疫复合物，细胞凋亡和效应T细胞在SLE发展中的作用。补体系统的紊乱是与多种形式的SLE特别是狼疮性肾炎的发生和进展密切相关。补体激活导致过敏毒素C3 a和C5 a的产生，其通过泛在表达的G蛋白偶联受体（C3 aR和C5 aR）。通过C3 aR和C5 aR信号传导在历史上被认为具有激活先天免疫反应的功能。本研究中包含的研究提出了C3 aR和C5 aR改变适应性免疫的定义和特征在人类疾病的生物学相关补体依赖性模型中的应答，即MRL/lpr 狼疮性肾炎的小鼠模型。具有C3 aR和C5 aR靶向缺失的小鼠以及C3 aR和C5 aR缺陷的小鼠， C3 aR和C5 aR都已经在MRL/lpr遗传背景上回交了9代。肾损伤与免疫反应包括抗原提呈细胞功能的比较研究，将进行T细胞和B细胞功能检查。此外，研究肾实质的实验根据细胞增殖、细胞外基质产生和细胞凋亡进行反应。这些研究旨在促进我们对补体作用机制的理解，活化产物调节免疫细胞中的细胞免疫应答和肾实质应答。介导的肾损伤。