Regulatory T Cell Modulation of the Alveolar Epithelium in Acute Lung Injury

急性肺损伤中肺泡上皮的调节性 T 细胞调节

基本信息

批准号：
8396464
负责人：
Jason Robert Mock
金额：
$ 5.1万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-20 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8396464
关键词：
Accounting Acute Acute Lung Injury Address Adoptive Transfer Adult Respiratory Distress Syndrome Affect Aging Alveolar Anti-Inflammatory Agents Anti-inflammatory Bacteria Blood capillaries Candida Cell Communication Cell Cycle Kinetics Cells Cessation of life Chronic Chronic Obstructive Airway Disease Coculture Techniques Color Data Development Diffuse Disease Edema Endotoxins Epithelial Epithelial Cells Epithelium Evaluation Extravasation Failure Fellowship Flow Cytometry Fluorescence-Activated Cell Sorting Gases Goals Human Hypoxemia IL2RA gene Immune response Immunofluorescence Immunologic Immunohistochemistry In Vitro Incidence Individual Inflammation Inflammation Mediators Injury Instruction Kinetics Laboratories Lead Life Liquid substance Lung Lung Inflammation Lung diseases Malignant Neoplasms Measurement Mentors Modeling Morbidity - disease rate Mus National Research Service Awards Natural regeneration Outcome Pathogenesis Patients Phase Phenotype Physicians Play Pneumonia Population Process Production Property Pseudomonas aeruginosa Pulmonary Fibrosis Recovery Recruitment Activity Regulatory T-Lymphocyte Research Resolution Role Scientist Signaling Molecule Stem cells Techniques Training United States Work alveolar epithelium capillary career development cell injury cell type chemokine cytokine design improved in vivo insight interest mortality novel novel therapeutics repaired research study response skills surfactant

项目摘要

DESCRIPTION (provided by applicant): The global objective of this NRSA Individual Fellowship Application is to facilitate development of essential skills that will allow the candidae to become an academic physician-scientist. The candidate and his mentor have designed a training plan that will include a rigorous research component along with didactic instruction to establish the thought processes and principles necessary for successful career development. Acute lung Injury (ALI) and the more severe Acute Respiratory Distress Syndrome (ARDS) are diffuse lung diseases characterized by hypoxemia, capillary leakage, edema, and epithelial cell damage. These processes cause tremendous morbidity and mortality in the United States each year. Despite decades of research into the pathogenesis underlying the development of ALI, mortality remains high. There is a paucity of information known about the resolution phase of ALI; however, Regulatory T cells (Tregs) have been demonstrated to be important in ALI resolution in a mouse endotoxin (LPS) administration model of ALI. Furthermore, Tregs have been detected to increase in bronchoalveolar fluid of patients with ARDS, suggesting that they may be important in the human immunological response to ALI. In acute or chronic injury the failure to regenerate the lung epithelium plays a role in such processes as acute lung injury, pneumonia, pulmonary fibrosis, cancer, COPD, and aging. Recently there has been considerable interest in investigating the cells types involved in repair along with the determinants which regulate these processes. The candidate has preliminary data demonstrating that the presence or absence of Tregs modulates alveolar epithelial repair. This novel finding of Treg modulation of the alveolar epithelium has not been previously described. The focus of this proposal is to further examine Treg effects on the alveolar epithelium during ALI resolution with the hope of identifying novel mechanisms that may lead to potential treatment options in patients with ALI. The specific aims proposed will utilize both in vivo and in vitro techniques to study Treg-alveolar epithelium interactions. In Specific Aim 1, examination of the effect of Tregs on the alveolar epithelial barrier during ALI resolution will be performed alon with evaluation of the alveolar epithelium using multi-color flow cytometry and immunohistochemistry to quantify in vivo epithelial changes. In Specific Aim 2, the impact Tregs exert on alveolar epithelial properties of phenotype and function will be determined through in vitro co-cultures of type II alveolar epithelial cells and Tregs. These experiments will explore new observations concerning Treg modulation of the alveolar epithelium during ALI with the ultimate goal of improving patient outcomes in this oftentimes fatal disease. PUBLIC HEALTH RELEVANCE: Acute lung injury (ALI) is a common pulmonary disease with high morbidity and mortality. Regulatory T Cells (Tregs) have been shown to be important in the resolution of ALI but their potential interaction and modulation of the alveolar epithelium in damage and repair is unknown. We propose to study Treg modulation of alveolar epithelial cells with the hope of identifying novel mechanisms that may ultimately lead to new therapeutic options for this disease.

描述（由申请人提供）：此 NRSA 个人奖学金申请的全球目标是促进基本技能的发展，使念珠菌成为学术医师科学家。候选人和他的导师设计了一个培训计划，其中包括严格的研究部分和教学指导，以建立成功职业发展所需的思维过程和原则。急性肺损伤 (ALI) 和更严重的急性呼吸窘迫综合征 (ARDS) 是弥漫性肺部疾病，其特征是低氧血症、毛细血管渗漏、水肿和上皮细胞损伤。这些过程每年在美国造成巨大的发病率和死亡率。尽管对 ALI 发病机制进行了数十年的研究，但死亡率仍然很高。关于 ALI 缓解阶段的已知信息很少；然而，在 ALI 的小鼠内毒素 (LPS) 给药模型中，调节性 T 细胞 (Treg) 已被证明对解决 ALI 具有重要作用。此外，已检测到 ARDS 患者的支气管肺泡液中 Tregs 数量增加，表明它们可能在人类对 ALI 的免疫反应中发挥重要作用。在急性或慢性损伤中，肺上皮再生失败在急性肺损伤、肺炎、肺纤维化、癌症、慢性阻塞性肺病和衰老等过程中发挥着重要作用。最近，人们对研究参与修复的细胞类型以及调节这些过程的决定因素产生了很大的兴趣。候选人有初步数据证明 Tregs 的存在或不存在可调节肺泡上皮修复。 Treg 调节肺泡上皮的这一新发现以前从未被描述过。该提案的重点是进一步检查 ALI 消退过程中 Treg 对肺泡上皮的影响，希望找出可能为 ALI 患者带来潜在治疗选择的新机制。提出的具体目标将利用体内和体内研究 Treg 与肺泡上皮相互作用的体外技术。在具体目标 1 中，将检查 ALI 消退过程中 Tregs 对肺泡上皮屏障的影响，同时使用多色流式细胞术和免疫组织化学评估肺泡上皮，以量化体内上皮变化。在具体目标 2 中，Tregs 对肺泡上皮表型和功能特性的影响将通过 II 型肺泡上皮细胞和 Tregs 的体外共培养来确定。这些实验将探索有关 ALI 期间 Treg 调节肺泡上皮的新观察结果，最终目标是改善这种常常致命的疾病的患者预后。公共卫生相关性：急性肺损伤（ALI）是一种常见的肺部疾病，发病率和死亡率很高。调节性 T 细胞 (Treg) 已被证明在 ALI 的解决中很重要，但它们在损伤和修复中对肺泡上皮的潜在相互作用和调节尚不清楚。我们建议研究肺泡上皮细胞的 Treg 调节，希望找到新的机制，最终为这种疾病带来新的治疗选择。