Epithelial/Dendritic cell cross-talk in acute kidney injury

急性肾损伤中的上皮/树突细胞串扰

基本信息

批准号：
8546337
负责人：
William Brian Reeves
金额：
$ 32.11万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-20 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8546337
关键词：
Acute Acute Renal Failure with Renal Papillary Necrosis Address Anti-Inflammatory Agents Anti-inflammatory Antigens Cell Survival Cells Cisplatin Clinical Clinical Trials Cues Cytoprotection Dendritic Cells Development Environment Epithelial Epithelial Cells Equilibrium Event Funding Gene Deletion Immune Immune system In Vitro Incidence Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injury Interleukin-10 Kidney Lead Leukocytes Mediating Modeling Pathogenesis Pathway interactions Phenotype Phosphorylation Play Prevention strategy Production Regulation Regulatory T-Lymphocyte Reporting Role STAT3 gene Severities Signal Transduction Site System T-Cell Activation T-Cell Receptor T-Lymphocyte TLR4 gene Therapeutic Tissues Transgenic Mice autocrine cytokine efficacy testing in vivo in vivo Model insight macrophage nephrotoxicity novel protective effect receptor receptor expression research study therapy design

项目摘要

DESCRIPTION (provided by applicant): Acute kidney injury (AKI) is a common and often fatal event. Inflammation plays a key role in the pathogenesis of AKI. Relatively little is known regarding the endogenous pathways which limit inflammation and reduce the incidence and/or severity of AKI. We recently determined that resident dendritic cells (DCs) and endogenous IL-10 are anti-inflammatory and reduce the severity of AKI. Moreover, the protective actions of dendritic cells are partially dependent upon their production of IL-10. The objective of this application is to delineate the mechanisms by which dendritic cells and endogenous IL-10 interact to reduce the severity of AKI. The central hypothesis is that a network of renal epithelial cells, dendritic cells and Treg cells, interacting through TLR receptors and IL-10, form a potent defense against acute kidney injury. In order to preserve the important contextual cues provided by the local cellular environment, our approach will emphasize in vivo models in pursuing an integrated analysis of anti-inflammatory mechanisms active in AKI through three aims. 1. Determine the mechanisms of regulation of dendritic cell (DC) IL-10 production and protection in AKI. We hypothesize that renal dendritic cells produce IL-10 and exert their anti-inflammatory and protective effects in AKI in a TLR4 and HO-1-dependent manner. 2. Determine the role of T cells in DC and IL-10 mediated protection against ARF. We hypothesize that resident dendritic cell protection in AKI is mediated through their ability to suppress antigen-specific activation of T cells and enhance IL- 10 production by Treg cells. 3. Determine the targets of IL-10 which mediate protection against AKI. We hypothesize that IL-10 reduces AKI by activating cell survival pathways in renal epithelial cells and reducing inflammatory cytokine production in both leukocytes and epithelial cells. These studies are unique as they integrate in vitro and in vivo approaches permitting detailed effector mechanisms to be defined and the pathophysiological relevance of the observations to be confirmed. These studies will provide new insights into this critical regulatory system. They will lead not only to a more complete understanding of cisplatin nephrotoxicity but also of other forms of AKI. The proposed studies have a translational underpinning in that they will stimulate the development of novel clinical interventions designed to abrogate the consequences of AKI.

描述（由申请人提供）：急性肾脏损伤（AKI）是一个常见且通常是致命的事件。炎症在AKI的发病机理中起关键作用。关于限制炎症并降低AKI的发生率和/或严重程度的内源性途径，知之甚少。我们最近确定居民树突状细胞（DC）和内源性IL-10具有抗炎作用，并降低了AKI的严重程度。此外，树突状细胞的保护作用部分取决于它们的IL-10产生。该应用的目的是描述树突状细胞和内源性IL-10相互作用以降低AKI的严重程度的机制。中心假设是，通过TLR受体和IL-10相互作用的肾上皮细胞，树突状细胞和Treg细胞网络形成了针对急性肾脏损伤的有效防御。为了保留局部细胞环境提供的重要上下文提示，我们的方法将在进行AKI通过三个目标的抗炎机制进行综合分析时强调体内模型。 1。确定AKI中树突状细胞（DC）IL-10的生产和保护的调节机制。我们假设肾脏树突状细胞产生IL-10并以TLR4和HO-1依赖性方式在AKI中发挥抗炎和保护作用。 2。确定T细胞在DC和IL-10介导的对ARF的保护中的作用。我们假设AKI中的驻留树突状细胞保护是通过抑制T细胞抗原特异性激活并通过Treg细胞增强IL-10产生的能力来介导的。 3。确定介导对AKI保护的IL-10的靶标。我们假设IL-10通过激活肾上皮细胞中的细胞存活途径并减少白细胞和上皮细胞的炎性细胞因子的产生来降低AKI。这些研究是独一无二的，因为它们在体外和体内方法整合，允许定义详细的效应机制以及要确认观察结果的病理生理相关性。这些研究将为这个关键的监管系统提供新的见解。他们不仅会更完整地了解顺铂肾毒性，而且还将对其他形式的AKI进行更全面的了解。拟议的研究具有转化的基础，因为它们将刺激旨在消除AKI后果的新型临床干预措施的发展。