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

• 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
• 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' 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

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.

靶向炎性细胞因子/趋化因子的异常表达 肾炎治疗 项目摘要/摘要 狼疮性肾炎(LN)是一种自身免疫性、免疫复合体介导的肾小球肾炎(GN)，是一种 系统性红斑狼疮(SLE)常见并发症。炎性介质的异常表达 LN早期和晚期均以组织损伤为特征。目前仍有未得到满足的治疗需求 减轻LN早期炎症和急性肾损伤向慢性损害转化的影响。 我们之前证明了MG53，最常见的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的表达 巨噬细胞。具有潜在的系统重要性的MG53循环和转基因小鼠具有持续的 循环MG53的提升具有正常寿命，但在以下情况下显示出增强的再生能力 组织损伤。在机制上，MG53与Tristetraprolin(TTP)相互作用，TTP是一种RNA结合蛋白，介导 信使核糖核酸3‘非编码区降解，一种通过调节许多基因表达来维持免疫平衡的效果 炎性细胞因子和趋化因子。我们推测，通过操纵循环中的MG53水平，我们将 能减轻狼疮性肾炎的肾脏炎症，防止组织损伤。这项提案将使用鼠标 遗传学、组织病理学、生化、分子细胞研究和显微成像来确定 能否长期维持循环MG53治疗LN。提出了两个具体目标。在Aim1， 我们将进行概念验证研究，以研究其抗炎和组织修复作用。 狼疮易感小鼠的循环MG53。一种新型DNA修饰微囊的可行性研究 将探索实现循环MG53井身稳定提升的输送系统。在目标2中，我们将阐明 MG53调控TTP信号调控表达的分子机制 炎性趋化因子单核细胞趋化蛋白-1(MCP-1)，作为MG53如何 用于控制活动期LN中细胞因子的表达。