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（由适用提供）：为了保留稳态和正常气体交换功能，肺必须限制对感染，抗原和毒素针对的持续攻击的炎症反应。远端肺中的宿主反应在很大程度上取决于牙槽上皮细胞（AEC）之间的串扰，该细胞（AEC）包含肺泡表面和肺泡巨噬细胞（AMS），即其驻留的免疫电池。关于AMS控制AEC的炎症反应的机制知之甚少。我们最近确定了一种新型的细胞间通信形式，其中AMS秘密补充剂的细胞因子信号传导（SOCS）1和3蛋白质中的膜中蛋白质蛋白可以在体外和IN VIVO中抑制炎症信号，以抑制炎症信号传导，以抑制炎症信号传导。某些生物活性分子（包括由AEC详细说明的分子）可以“调整” SOC的AM分泌。此外，吸烟减少，而腺病毒感染会增加肺灌洗液中的SOC水平，表明SOCS分泌失调与表征这些疾病的炎症反应的已知变化有关。该建议旨在更好地了解这种新型AM-AEC跨话的基本机制，生物学后果和治疗后果。 AIM 1将表征释放两种不同类型的蔬菜（微粒和外泌体）的机制，以及内部SOCS蛋白的分泌，以响应生物活性分子以及AEC衍生的因素。 AIM 2将确定控制这些不同SOC蔬菜在AEC中吸收的机制，以及跨细胞SOC递送对靶细胞中细胞因子信号传导，炎症基因表达，增殖和凋亡的影响。 AIM 3将表征在吸烟和腺病毒感染引起的急性炎症的小鼠模型中，SOCS分泌失调的工作机制和后果。此外，将在体外和体内测试带有重组SOCS蛋白的合成脂质体蔬菜的作用和治疗潜力。这些研究将为调节肺部感染的调节以及一种新型治疗方法的控制提供新的见解。