Secreted SOCS Proteins as Vectors of Lung Macrophage to Epithelial Cell Crosstalk

分泌的 SOCS 蛋白作为肺巨噬细胞与上皮细胞串扰的载体

基本信息

批准号：
9257198
负责人：
MARC L PETERS-GOLDEN
金额：
$ 57.78万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9257198
关键词：
Acute Alveolar Alveolar Macrophages Anatomy Anti-Inflammatory Agents Anti-inflammatory Antigens Apoptosis Biological Bronchoalveolar Lavage Fluid CISH gene Cell physiology Cells Code Color Communicable Diseases Cytokine Signaling Development Distal Elements Encapsulated Epithelial Cells Extracellular Space Family Foundations Gases Gene Expression Growth Factor Homeostasis Human Immune Immune response In Vitro Infection Inflammation Inflammatory Inflammatory Response Injection of therapeutic agent Janus kinase Laboratories Lipopolysaccharides Liposomes Lung Lung Inflammation Lung Lavage Fluid Maintenance Membrane Phenotype Physiological Process Property Proteins Pulmonary Inflammation Recombinants Regulation Rodent Role STAT protein Scheme Signal Transduction Signaling Protein Surface Testing Therapeutic Tissues Toxin Transcriptional Activation Vesicle Work assault cigarette smoking cytokine exosome in vitro testing in vivo insight intercellular communication macrophage member mouse model novel novel therapeutic intervention paracrine public health relevance response restraint uptake vector

项目摘要

DESCRIPTION (provided by applicant): In order to preserve homeostasis and normal gas exchange function, the lung must restrain inflammatory responses to the continual assault posed by infections, antigens, and toxins. Host responses in the distal lung are dictated in large part by the cross-talk between alveolar epithelial cells (AECs), which comprise the alveolar surface, and alveolar macrophages (AMs), its resident immune cells. Little is known about mechanisms by which AMs control inflammatory responses of AECs. We have recently identified a novel form of intercellular communication in which AMs secrete suppressors of cytokine signaling (SOCS) 1 and 3 proteins within membrane-delimited vesicles that can be taken up by AECs to inhibit inflammatory signaling in response to cytokines in vitro and in vivo. AM secretion of SOCS can be "tuned" by certain bioactive molecules, including those elaborated by AECs. Furthermore, cigarette smoking reduces while adenoviral infection increases SOCS levels in lung lavage fluid, indicating that dysregulation of SOCS secretion is associated with the known alterations in inflammatory responses that characterize these conditions. This proposal seeks to better understand the fundamental mechanisms, biological consequences, and therapeutic ramifications of this novel form of AM-AEC cross-talk. Aim 1 will characterize mechanisms regulating the release of two distinct types of vesicles - microparticles and exosomes - and the secretion of SOCS proteins within them, in response to bioactive molecules as well as AEC-derived factors. Aim 2 will determine the mechanisms controlling uptake of these distinct SOCS-containing vesicles in AECs and the effects of transcellular SOCS delivery on cytokine signaling, inflammatory gene expression, proliferation, and apoptosis in the target cells. Aim 3 will characterize the operative mechanisms for and consequences of dysregulated SOCS secretion in mouse models of acute inflammation induced by cigarette smoking and adenoviral infection. In addition, the effects and therapeutic potential of synthetic liposomal vesicles loaded with recombinant SOCS proteins will be tested in vitro and in vivo. These studies will provide new insights into the regulation of lung inflammation and a foundation for a novel therapeutic approach to its control.

描述（由申请人提供）：为了保持体内平衡和正常的气体交换功能，肺部必须抑制对感染、抗原和毒素持续攻击的炎症反应。远端肺部的宿主反应在很大程度上取决于肺部。肺泡上皮细胞（AEC）（包括肺泡表面）和肺泡巨噬细胞（AM）（其常驻免疫细胞）之间的串扰机制知之甚少。 AM 控制 AEC 的炎症反应。我们最近发现了一种新的细胞间通讯形式，其中 AM 会在膜界定的囊泡内分泌细胞因子信号传导抑制物 (SOCS) 1 和 3 蛋白，这些蛋白可以被 AEC 摄取以抑制炎症信号传导。 SOCS 的 AM 分泌可通过某些生物活性分子（包括 AEC 所产生的分子）“调节”。此外，吸烟可减少腺病毒感染。增加肺灌洗液中的 SOCS 水平，表明 SOCS 分泌失调与已知的炎症反应变化有关，而炎症反应是这些疾病的特征。该提案旨在更好地了解这种新型 AM 的基本机制、生物学后果和治疗后果。 -AEC 串扰将表征调节两种不同类型囊泡（微粒和外泌体）的释放以及其中 SOCS 蛋白的分泌的机制，以响应生物活性分子和生物活性分子。 AEC 衍生因子将描述控制 AEC 中这些不同的含有 SOCS 的囊泡的摄取的机制，以及跨细胞 SOCS 递送对细胞因子信号传导、炎症决定的靶细胞中的基因表达、增殖和凋亡的影响。吸烟和腺病毒感染引起的急性炎症小鼠模型中 SOCS 分泌失调的作用机制和后果此外，合成脂质体的作用和治疗潜力。装载有重组 SOCS 蛋白的囊泡将在体外和体内进行测试，这些研究将为肺部炎症的调节提供新的见解，并为控制炎症的新治疗方法奠定基础。