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Pathogenesis of Lupus Nephritis

狼疮性肾炎的发病机制

基本信息

批准号：
10612792
负责人：
Joseph Edgar Craft
金额：
$ 61.1万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-06 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10612792
关键词：
Address Affect Antigen-Antibody Complex Autoantibodies Automobile Driving B-Cell Activation B-Lymphocytes Blood Cells CD8-Positive T-Lymphocytes CD8B1 gene Cell Maturation Cell Survival Cell physiology Cells Cellular Metabolic Process Characteristics Chromatin Data Deposition Ensure Environment Environmental Risk Factor Epigenetic Process Event Genetic Genetic Transcription Goals Human Hypoxia Immune Immune Complex Glomerulonephritis In Situ In Vitro Infiltration Inflammation Inflammatory Inflammatory Response Injury Injury to Kidney Interruption Kidney Knowledge Lupus Lupus Nephritis Lymphocyte Metabolic Microscopic Modeling Modification Morbidity - disease rate Mus Outcome Oxygen Pathogenesis Pathogenicity Pathway interactions Patients Phenotype Physiological Production Regulation Severity of illness Shapes Site Spleen Stress Systemic Lupus Erythematosus T cell infiltration T-Cell Activation T-Lymphocyte Therapeutic Therapeutic Agents Tissues Work autoreactive B cell autoreactive T cell effector T cell environmental adaptation epigenome genetic manipulation hypoxia inducible factor 1 immune cell infiltrate immunoregulation in vivo inflammatory milieu kidney biopsy mortality novel organ injury pathogen pathogenic autoantibodies peripheral blood pharmacologic phase I trial prevent programmed cell death protein 1 public health relevance renal damage renal hypoxia response secondary lymphoid organ therapeutic target tissue injury transcription factor tumor

项目摘要

PROJECT SUMMARY (ABSTRACT) Lupus nephritis occurs in a majority of patients with systemic lupus erythematosus (SLE, lupus), and is a leading cause of morbidity and mortality. CD4+ and CD8+ T effector cells contribute to the inflammatory response in lupus nephritis in mice and in humans with their renal infiltration correlated to tissue damage and disease severity. Yet, there is limited knowledge of the phenotypic characteristics of the T cells that promote local tissue injury in lupus. The kidney microenvironment becomes hypoxic as a common denominator following a variety of insults, an appropriately physiologic response analogous to that which occurs to ensure lymphocyte survival and effector function during environmental stress, such as at sites of pathogen replication or in tumors. We have shown in preliminary studies that this response in the murine lupus kidney results in tissue adaptive transcriptional and phenotypic changes in renal infiltrating T cells, changes associated with epigenetic modification, with evidence that analogous changes occur in human lupus nephritis. We now propose in this revised application sto explore the hypothesis that environmental stress in the lupus kidney necessarily shapes the phenotypes of renal-infiltrating T cells, with programming for survival and effector function, culminating in tissue injury. We will explore this hypothesis using in vitro and in vivo studies, including genetic and pharmacologic manipulation of tissue adaptive effector pathways in renal T cells, with target confirmation in human lupus nephritis. Our longer term goal, if the current project is successful, is to use this knowledge to re-purpose therapeutic agents currently available for use in humans to treat lupus nephritis.

项目概要（摘要）狼疮性肾炎发生在大多数系统性红斑狼疮（SLE，狼疮）患者中，是一种慢性肾炎。发病率和死亡率的主要原因。CD4+和CD8+ T效应细胞有助于炎症反应。小鼠和人类狼疮性肾炎的反应，其肾脏浸润与组织损伤相关，疾病严重程度。然而，对于促进免疫应答的T细胞的表型特征的知识有限。局部组织损伤肾脏微环境变得缺氧作为一个共同点在各种损伤之后，适当的生理反应类似于发生以确保环境应激期间淋巴细胞存活和效应子功能，例如在病原体复制部位或在肿瘤中。我们已经在初步研究中表明，这种反应在小鼠狼疮肾的结果，肾浸润性T细胞的组织适应性转录和表型变化，表观遗传修饰，有证据表明，类似的变化发生在人类狼疮肾炎。我们现在在这份修订后的申请中，我提议探讨狼疮肾中的环境应激这一假设，必然塑造肾脏浸润性T细胞的表型，并对存活和效应细胞进行编程。功能，最终导致组织损伤。我们将使用体外和体内研究来探讨这一假设，包括肾T细胞中组织适应性效应子途径的遗传和药理学操作，狼疮性肾炎的诊断我们的长期目标是，如果目前的项目成功，重新利用目前可用于人类治疗狼疮性肾炎的治疗剂的知识。