Targeting Aberrant Expression of Cytokines/Chemokines for an Inflammatory Nephritis Cure

针对细胞因子/趋化因子的异常表达来治疗炎症性肾炎

基本信息

批准号：
10525534
负责人：
Pei-Hui Lin
金额：
$ 23.63万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-22 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10525534
关键词：
3&apos Untranslated Regions Ablation Acute Acute Renal Failure with Renal Papillary Necrosis Address Affect Anti-Inflammatory Agents Antigen-Antibody Complex Antinuclear Antibodies Apoptotic Attenuated Autoantibodies Autoantigens Autoimmune Biochemical Biological Markers Blood Circulation CCL2 gene Cell membrane Cells Cellular biology Chronic Complication Contrast Media DNA Data Deposition Development Distant Event Exposure to Genes Genetic Genetic Predisposition to Disease Glomerulonephritis Homeostasis Hormonal Immune Immunology In Vitro Inflammation Inflammation Mediators Inflammatory Injury Injury to Kidney Ischemia Kidney Kidney Diseases Knowledge Lead Link Longevity Lupus Lupus Nephritis Mediating Mediator of activation protein Membrane Messenger RNA Modeling Molecular Molecular Biology Mouse Strains Mus Muscle Fibers Muscle Proteins Nephritis Nuclear Organ Organism Pathogenesis Pathogenicity Pathology Patients Phase Phenotype Physical Function Physical activity Play Production Protein Family Proteins Proteinuria RNA RNA-Binding Proteins Regenerative capacity Regulation Renal function Reperfusion Therapy Role Self Tolerance Serum Signal Transduction Skeletal Muscle Spleen Stimulus System Systemic Lupus Erythematosus TIS11 protein TRIM Motif Tissues Transgenic Mice Tubular formation Ureteral obstruction Urine Viral Virus Diseases cell injury cell type cellular imaging chemokine cytokine cytokine release syndrome design imaging study immunoregulation inflammatory modulation kidney cell knock-down lung injury lupus prone mice lymph nodes macrophage microscopic imaging microvesicles mouse genetics mouse model novel overexpression particle prevent recruit regeneration following injury renal damage repaired tissue injury tissue regeneration tissue repair urinary

项目摘要

TARGETING ABERRANT EXPRESSION OF CYTOKINES/CHEMOKINES FOR AN INFLAMMATORY NEPHRITIS CURE PROJECT SUMMARY / ABSTRACT Lupus nephritis (LN) is an autoimmune, immune complex-mediated glomerulonephritis (GN), which is a frequent complication of systemic lupus erythematosus (SLE). Aberrant expression of inflammatory mediators and tissue injury characterize the early and later stages of LN. There is ongoing unmet need for therapies to attenuate the effects of early inflammation and the conversion of acute kidney injury to chronic damage in LN. We previously demonstrated that MG53, most commonly recognized as protein product of skeletal muscles, can mediate repair of damaged cell membranes, and can modulate cytokine expression in virally-infected macrophage. Of potential systemic importance, MG53 circulates and transgenic mice with a sustained elevation of circulating MG53 have a normal lifespan, but show enhanced regenerative capacity following a tissue injury. Mechanistically, MG53 interacts with tristetraprolin (TTP), a RNA binding protein that mediates mRNA 3’UTR degradation, an effect that maintains immune homeostasis by regulating the expression of many inflammatory cytokines and chemokines. We postulated that by manipulating circulating MG53 levels we will be able to attenuate renal inflammation and prevent tissue damage in LN. This proposal will use mouse genetics, tissue pathology, biochemical, molecular cellular studies and microscopy imaging to determine whether circulating MG53 can be sustained chronically to treat LN. Two specific aims are proposed. In Aim1, we will perform proof-of-concept studies to investigate the anti-inflammatory and tissue-repair effects of circulating MG53 in well-characterized lupus-prone mice. The feasibility of a novel DNA-modified microvesicle delivery system to achieve a stable elevation of circulating MG53 will be explored. In Aim 2, we will elucidate the underlying molecular mechanisms of MG53-mediated control of TTP signaling to modulate the expression of the inflammatory chemokine monocyte chemoattractant protein-1 (MCP-1), as a model for how MG53 may be used to control cytokine expression in active LN.

针对炎症细胞因子/趋化因子的异常表达肾炎治愈项目概要/摘要狼疮性肾炎 (LN) 是一种自身免疫性、免疫复合物介导的肾小球肾炎 (GN)，系统性红斑狼疮（SLE）的常见并发症。炎症介质的异常表达。 LN 早期和晚期的特征是组织损伤和组织损伤，目前对治疗的需求尚未得到满足。减轻早期炎症的影响以及急性肾损伤向慢性肾损伤的转化。我们之前证明了 MG53，最常被认为是骨骼肌的蛋白质产物，可以介导受损细胞膜的修复，并可以调节病毒感染的细胞因子表达 MG53 具有潜在的系统重要性，对转基因小鼠具有持续的作用。循环 MG53 升高具有正常的寿命，但在从机制上讲，MG53 与 tristetraprolin (TTP) 相互作用，TTP 是一种介导的 RNA 结合蛋白。 mRNA 3'UTR 降解，通过调节许多因子的表达来维持免疫稳态的效应我们假设通过控制循环 MG53 水平，我们将能够抑制炎症细胞因子和趋化因子。能够减轻肾炎症并防止 LN 组织损伤该提案将使用小鼠。遗传学、组织病理学、生物化学、分子细胞研究和显微镜成像来确定是否可以长期维持循环 MG53 来治疗 LN。在 Aim1 中提出了两个具体目标。我们将进行概念验证研究，以研究其抗炎和组织修复作用一种新型 DNA 修饰微泡的可行性。在目标 2 中，我们将探讨实现循环 MG53 稳定升高的递送系统。 MG53介导的TTP信号控制控制表达的潜在分子机制炎症趋化因子单核细胞趋化蛋白-1 (MCP-1)，作为 MG53 如何发挥作用的模型用于控制活性 LN 中的细胞因子表达。