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

• 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
• 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

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）：该NRSA个别奖学金申请的全球目标是促进基本技能的发展，这将使Candidae成为学术医师科学家。候选人及其导师设计了一项培训计划，该计划将包括一个严格的研究组成部分以及教学指导，以建立成功的职业发展所必需的思考过程和原则。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引起巨大的发病率和死亡率。尽管数十年来研究了ALI发展的基础发病机理，但死亡率仍然很高。关于阿里的分辨率阶段的信息很少。然而，已证明调节性T细胞（Treg）在ALI的小鼠内毒素（LPS）给药模型中的ALI分辨率中很重要。此外，已经检测到Tregs增加了ARDS患者的支气管肺泡液的增加，这表明它们在人类对ALI的免疫反应中可能很重要。在急性或慢性损伤中，未能再生肺上皮在急性肺损伤，肺炎，肺纤维化，癌症，COPD和衰老等过程中起作用。最近，人们对研究修复的细胞类型以及调节这些过程的决定因素引起了极大的兴趣。候选人的初步数据表明，Treg的存在或不存在调节肺泡上皮修复。先前尚未描述这种牙槽上皮的Treg调节的新发现。该提案的重点是进一步研究ALI分辨率期间对肺泡上皮的影响，以期识别出可能导致ALI患者潜在治疗选择的新型机制。提出的具体目的将利用体内和 研究Treg-肺泡上皮相互作用的体外技术。在特定的目标1中，使用多色流式细胞仪和免疫组织化学来评估Treg对ALI分辨率期间肺泡上皮屏障的影响，以量化体内上皮上皮变化。在特定的目标2中，将通过体外共培养II型肺泡上皮细胞和Tregs的体外共培养来确定表型和功能肺泡上皮性能的影响。这些实验将探讨有关在ALI期间牙槽上皮调节的新观察结果，其最终目的是改善这种致命疾病的患者结局。 公共卫生相关性：急性肺损伤（ALI）是一种常见的肺部疾病，发病率高和死亡率。调节性T细胞（TREG）已显示在ALI的分辨率中很重要，但是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，以期识别新的机制，这些机制最终可能导致该疾病的新治疗选择。