Regulatory T Cells Promote Alveolar Epithelial Repair

调节性 T 细胞促进肺泡上皮修复

• 批准号: 9180313
• 负责人: Jason Robert Mock
• 金额: $ 17.11万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9180313
• 关键词: AGTR2 gene; Acute; Acute Lung Injury; Address; Adhesions; Adult Respiratory Distress Syndrome; Advisory Committees; Affect; Aging; Alveolar; Anti-Inflammatory Agents; Anti-inflammatory; Antigen-Antibody Complex; Apoptotic; Award; Basic Science; Binding; Biological; Blood capillaries; Cells; Chronic; Chronic Obstructive Airway Disease; Clinical; Cues; Data; Development; Disease; E-Cadherin; Edema; Epithelial; Epithelial Cell Proliferation; Epithelial Cells; Epithelium; Extravasation; Failure; Gases; Goals; Growth; Human; Hypoxemia; Immune; Immune response; In Vitro; Inflammation; Injury; Instruction; Integrins; Intensive Care Units; Kinetics; Lead; Liquid substance; Lung; Lung Inflammation; Lung diseases; Lymphocyte; Malignant Neoplasms; Mediating; Mediator of activation protein; Medical; Mentors; Morbidity - disease rate; Natural regeneration; Parents; Patient Care; Patient-Focused Outcomes; Patients; Phase; Physicians; Play; Pneumonia; Process; Publishing; Pulmonary Fibrosis; R-cadherin; Recovery; Recruitment Activity; Regulation; Regulatory T-Lymphocyte; Reporting; Research; Resolution; Role; Scientist; Signal Transduction; Signaling Molecule; Site; Surface; T-Lymphocyte; Techniques; Testing; Time; Tissues; Training; Translations; Work; alveolar epithelium; alveolar type II cell; capillary; career; career development; cell injury; cell type; design; experience; improved; in vivo; interest; keratinocyte growth factor; lung injury; mortality; novel; novel therapeutics; repaired; response; skills; surfactant; surfactant production

Project Summary The global objective of this K08 Mentored Clinical Scientist Career Award Application is to facilitate development of essential skills that will allow the candidate to become an academic physician-scientist. The proposal provides not only new techniques but even more importantly an understanding of the biological significance of the observations and ideas about their translation toward applicability in the care of patients. The candidate, his mentor and his advisory committee have designed a training plan that includes a rigorous research component along with didactic instruction to establish the thought processes and principles necessary for successful career development. Through coursework and practical experience the candidate will develop a deeper understanding of the complex immune mechanisms that underlie the development and resolution of lung injury. His clinical work in the medical intensive care unit caring for patients with severe lung disease will inform his basic research practices as well as guide the translation of that work to patient care. Acute Respiratory Distress Syndrome (ARDS) is characterized by hypoxemia, capillary leakage, edema, and epithelial cell damage and causes high morbidity and mortality in the U.S. each year. There is a paucity of information about the resolution phase of acute lung injury (ALI); however, published work has demonstrated a role for Foxp3+ regulatory T cells (Tregs) in the resolution of experimental ALI. Furthermore, Tregs increase in bronchoalveolar fluid of patients with ARDS, suggesting that they are important in the human immunological response to lung injury. In acute or chronic injury the failure to regenerate the lung epithelium plays a role in such processes as ALI, pneumonia, pulmonary fibrosis, cancer, COPD, and aging. Recently there has been considerable interest in the cell types involved in repair and the regulation of this process. The candidate’s data demonstrate that the presence of Tregs enhances alveolar epithelial repair, a novel finding that has not been previously described. This proposal examines 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 ARDS. The specific aims utilize both in vivo and in vitro techniques to study the interactions between Tregs and alveolar epithelium. Aim 1 investigates the role of CD103 expression on Treg in ALI resolution and tests the hypothesis that CD103 promotes epithelial repair by retaining Tregs at epithelial sites of inflammation and enhancing their tissue reparative effects. Aim 2 determines the impact of Treg-expressed KGF in ALI resolution, hypothesizing that this KGF promotes epithelial kinetics, surfactant expression, and barrier integrity. Aim 3 determinates the contribution of Treg-derived microparticles to ALI resolution, hypothesizing that Treg-derived microparticles communicate with the alveolar epithelium to amplify resolution of lung inflammation. These studies will explore new observations concerning Treg modulation of the alveolar epithelium during ARDS resolution with the ultimate goal of improving patient outcomes in this often times fatal disease.

项目摘要 K 08指导临床科学家职业奖申请的全球目标是促进发展 这些基本技能将使候选人成为一名学术物理学家。该提案规定， 不仅是新技术，更重要的是对生物学意义的理解， 关于其在患者护理中的适用性的翻译的观察和想法。候选人，他的 曼特和他的顾问委员会设计了一个培训计划，其中包括一个严格的研究部分 沿着教学指导，以建立成功职业生涯所需的思维过程和原则 发展通过课程和实践经验，候选人将发展更深的理解 复杂的免疫机制，肺损伤的发展和解决的基础。他的临床工作 在重症监护室照顾严重肺部疾病患者将告知他的基础研究 实践，并指导将这项工作转化为病人护理。急性呼吸窘迫综合征 急性呼吸窘迫综合征（ARDS）的特征在于低氧血症、毛细血管渗漏、水肿和上皮细胞损伤，并引起高血压。 美国每年的发病率和死亡率。目前，关于解决方案阶段的信息很少。 急性肺损伤（ALI）;然而，已发表的工作已经证明Foxp 3+调节性T细胞（TCFs）在急性肺损伤中的作用。 实验性ALI的解决方案。此外，ARDS患者的支气管肺泡液中TdR增加， 这表明它们在人类对肺损伤的免疫应答中是重要的。急性或慢性损伤 肺上皮再生的失败在诸如ALI、肺炎、肺损伤、肺损伤、肺栓塞、肺栓塞等过程中起作用。 纤维化、癌症、COPD和衰老。最近，人们对参与细胞分化的细胞类型产生了相当大的兴趣。 修复和调节这个过程。候选人的数据表明，TdR的存在增强了 肺泡上皮修复，一个新的发现，以前没有描述。本提案审查Treg 在ALI消退过程中对肺泡上皮细胞的影响，希望能确定新的机制， 为ARDS患者提供了潜在的治疗选择。具体目标是利用体内和体外 技术来研究TdR和肺泡上皮之间的相互作用。目的1研究CD 103的作用 在ALI消退中CD 103对Treg表达的影响，并检验了CD 103通过保留 在炎症的上皮部位，并增强其组织修复作用。目标2决定影响 Treg表达的KGF在ALI消退中的作用，假设这种KGF促进上皮动力学，表面活性剂 表达和屏障完整性。目的3确定Treg衍生的微粒对ALI的贡献 分辨率，假设Treg衍生的微粒与肺泡上皮细胞通讯，以扩增 肺部炎症消退。这些研究将探索关于Treg调节的新观察， 肺泡上皮细胞在ARDS决议的最终目标是改善病人的结果，在这往往 倍致命的疾病。