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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：
10651843
负责人：
Pei-Hui Lin
金额：
$ 19.69万
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 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10651843
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 CCL2 gene Cell membrane Cells Cellular biology Chronic Circulation Complication Contrast Media DNA Data Deposition Development Distant Early Diagnosis 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 Macrophage Mediating Mediator 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 chemokine cytokine cytokine release syndrome design imaging study immunoregulation inflammatory modulation kidney cell knock-down lung injury lupus prone mice lymph nodes 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.

针对异常表达的细胞因子/趋化因子的炎症