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

靶向细胞因子/趋化因子的异常表达用于炎症 肾炎治疗 项目总结/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 组织损伤是LN早期和晚期的特征。目前仍存在未满足的治疗需求， 减轻LN早期炎症的影响和急性肾损伤向慢性损伤的转化。 我们以前证明了MG 53，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中细胞因子的表达， 巨噬细胞具有潜在的全身重要性，MG 53循环和转基因小鼠具有持续的 循环MG 53的升高具有正常的寿命，但显示出增强的再生能力， 组织损伤在机制上，MG 53与tristetraprolin（TTP）相互作用，TTP是一种RNA结合蛋白，介导 mRNA 3 'UTR降解是一种通过调节许多免疫调节因子的表达来维持免疫稳态的作用。 炎性细胞因子和趋化因子。我们假设，通过操纵循环中的MG 53水平， 能够减轻LN中的肾脏炎症并防止组织损伤。这个建议将使用鼠标 遗传学、组织病理学、生物化学、分子细胞研究和显微镜成像，以确定 循环MG 53是否可以长期维持以治疗LN。提出了两个具体目标。在目标1中， 我们将进行概念验证研究，以调查 在充分表征的狼疮易感小鼠中的循环MG 53。一种新型DNA修饰微泡的可行性研究 将探索用于实现循环MG 53的稳定升高的递送系统。在目标2中，我们将阐明 MG 53介导的TTP信号转导调控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MG 53如何 用于控制活动性LN中细胞因子的表达。

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.