Role of GPR116 in Alveolar Homeostasis

GPR116 在肺泡稳态中的作用

基本信息

批准号：
9078096
负责人：
James Patrick Bridges
金额：
$ 40.26万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-18 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9078096
关键词：
Actins Acute Lung Injury Adult Alveolar Alveolar Macrophages Amino Acids Attenuated Biological Assay Breathing Cell membrane Cells Child Coupled Data Disease Epithelial Epithelial Cells Epithelium Equilibrium F-Actin Functional disorder G-Protein-Coupled Receptors GTP-Binding Proteins Gases Genetic Goals Homeostasis Human In Vitro Infant respiratory distress Inflammation Lipid Peroxidation Lung Lung diseases Mediating Modeling Molecular Molecular Target Mus Neutrophilia Orphan Oxidative Stress Pathogenesis Pathologic Pathway interactions Patients Phospholipids Physiological Proteins Pulmonary Alveolar Proteinosis Pulmonary Surfactants Respiratory Failure Role Signal Pathway Signal Transduction Source Structure of parenchyma of lung Testing Therapeutic Tissues Type II Epithelial Receptor Cell Wild Type Mouse Work alveolar homeostasis alveolar type II cell base clinically relevant in vivo insight loss of function mRNA Expression mouse model novel peroxidation phosphoproteomics pre-clinical prevent public health relevance release of sequestered calcium ion into cytoplasm respiratory distress syndrome surfactant synthetic peptide therapeutic target uptake

项目摘要

DESCRIPTION (provided by applicant): Pulmonary alveolar homeostasis is dependent upon balanced airway and tissue surfactant pools. Quantitative and qualitative alterations in alveolar surfactant pools are associated with inflammation and tissue destruction in severe lung diseases including infant respiratory distress syndrome, many forms of acute lung injury and pulmonary alveolar proteinosis. Identification of a physiologically-dominant molecular pathway within alveolar epithelial cells that senses and regulates endogenous alveolar surfactant pools, coupled with the ability to pharmacologically modulate it both positively and negatively, would be a major therapeutic advance for patients with lung diseases associated with pulmonary surfactant disorders. Preliminary data supporting this application strongly implicate an alveolar epithelial cell-centric, G protein-dependent pathway driven by GPR116 as a druggable molecular target to modulate endogenous alveolar surfactant pools. We demonstrate that GPR116 is abundantly expressed in human and mouse lung, and pulmonary epithelium-specific deletion of GPR116 in mice results in early and progressive accumulation of alveolar surfactant associated with phospholipid peroxidation, neutrophilia and alveolar remodeling, culminating in respiratory failure. We have identified a novel synthetic peptide that is sufficient to activate G protein-dependent signaling downstream of mouse and human GPR116 in vitro and suppress alveolar surfactant levels in mice in vivo, providing proof-of- concept that GPR116 is a plausible therapeutic target to modulate endogenous alveolar surfactant pools in humans. Our central hypothesis is that epithelial GPR116 regulates alveolar surfactant homeostasis via Gq/11- driven modulation of actin cytoskeletal dynamics in alveolar type II cells. Our goal in this projec is to systematically define the signaling pathways by which GPR116 controls surfactant homeostasis using cell-based assays and mouse genetics through completion of three integrated aims. In the first aim, we will test the hypothesis that GPR116-dependent activation of a Gq/G11-PKCδ-dependent pathway induces cortical F-actin assembly to suppress surfactant secretion and/or decrease surfactant uptake in alveolar type II cells. In the second aim, we will test the hypothesis that activation of epithelial GPR116 is sufficient to restore surfactant homeostasis in two established mouse models of alveolar surfactant overload, Csf2rb-/- and Sftpd-/- mice. In the third aim, we will test the hypothesis that increased alveolar surfactant pools initiate alveolar macrophage oxidative stress and subsequent alveolar simplification in Gpr116-/- mice. Successful completion of these specific aims will delineate the signaling pathways by which GPR116 senses and regulates surfactant and alveolar homeostasis. The long-term goal of this work is to identify potential therapeutic targets, including GPR116 itself, that will permit modulation of endogenous surfactant levels to treat human lung diseases associated with surfactant dysfunction.

描述（由适用提供）：肺肺泡稳态取决于平衡气道和组织表面活性剂池。肺泡表面活性剂池的定量和定性改变与包括婴儿呼吸障碍综合征，许多形式的急性肺损伤和肺肺泡蛋白质病在内的严重肺部疾病的感染和组织破坏有关。鉴定异形上皮细胞内的物理优势分子途径，该途径感知和调节内源性肺泡表面活性剂池，再加上对与肺部疾病疾病相关的患者的主要治疗疗法，可以对其进行积极和负面的身体调节。支持该应用的初步数据强烈暗示了由GPR116驱动的肺泡上皮细胞中心，G蛋白依赖性途径作为可药物的分子，我们已经确定了一种足以激活G蛋白依赖性的新型合成肽。小鼠和人类GPR116在体外的体外和抑制肺泡表面活性剂水平的信号传导，提供了概念概念，表明GPR116是一个合理的治疗靶标，可以调节人类中内源性肺泡表面活性池。我们的中心假设是，上皮GPR116通过gQ/11驱动的II型细胞中肌动蛋白细胞骨架动力学调节肺泡表面活性剂稳态。我们在此ProJEC中的目标是系统地定义GPR116通过基于细胞的测定和小鼠遗传学来控制表面活性剂稳态的信号通路，并通过完成三个综合目标。在第一个目标中，我们将检验以下假设：GPR116依赖性GQ/G11-PKCΔ依赖性途径诱导皮质F-肌动蛋白组装抑制表面活性剂的分泌和/或降低肺泡II型细胞中的表面活性剂的摄取。在第二个目标中，我们将检验以下假设：上皮GPR116的激活足以恢复两个已建立的肺泡表面活性剂过载的小鼠模型CSF2RB-/ - 和SFTPD - / - / - 小鼠的生存稳态。在第三个目标中，我们将检验以下假设：增加肺泡表面活性池启动肺泡巨噬细胞氧化应激，并在GPR116 - / - 小鼠中进行随后的肺泡简化。这些特定目标的成功完成将描述GPR116感觉和调节基础和肺泡稳态的信号通路。这项工作的长期目标是确定包括GPR116本身在内的潜在治疗靶标，该靶标将允许调节内源性基础水平，以治疗与潜在功能障碍相关的人类肺部疾病。