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; 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 该K08指导的临床科学家职业奖的全球目标是促进发展 基本技能将使候选人成为学术的身体科学家。提案提供 不仅是新技术，更重要的是了解对生物学意义的理解 关于它们在患者护理中的适用性转化的观察和想法。候选人，他的 导师及其咨询委员会设计了一个培训计划，其中包括严格的研究组成部分 以及教学教学以建立成功职业所必需的思维过程和原则 发展。通过课程和实践经验，候选人将有更深入的了解 基于肺损伤发展和解决的复杂免疫机制。他的临床工作 在携带严重肺部患者的医疗重症监护病房中，将为他的基础研究提供信息 实践以及指导该工作将其转化为患者护理。急性呼吸窘迫综合征 （ARDS）的特征是低氧血症，毛细血管泄漏，水肿和上皮细胞损伤，并导致高 美国每年的发病率和死亡率。关于解决阶段的信息很少 急性肺损伤（ALI）；但是，已发表的工作表明了Foxp3+调节性T细胞（TREG）在 实验ALI的分辨率。此外，ARDS患者的支气管肺泡液的Tregs增加， 表明它们在人类对肺损伤的免疫反应中很重要。急性或慢性损伤 未能再生肺上皮在诸如Ali，肺炎，肺部的过程中起作用 纤维化，癌症，COPD和衰老。最近，人们对涉及的细胞类型引起了极大的兴趣 维修和该过程的调节。候选人的数据表明，Tregs增强功能的存在 肺泡上皮修复，这是一种尚未描述的新发现。此提案考试Treg 在ALI分辨率期间对肺泡上皮的影响，希望鉴定出可能的新机制 导致ARDS患者的潜在治疗选择。具体目的是利用体内和体外 研究Tregs和肺泡上皮之间相互作用的技术。 AIM 1研究CD103的作用 在ALI分辨率中对Treg的表达，并检验了CD103通过保留促进上皮修复的假设 炎症上皮部位的Tregs并增强其组织的修复作用。目标2决定了影响 treg表达的kgf在ALI分辨率中，假设该KGF促进上皮动力学，表面活性剂 表达和障碍完整性。 AIM 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进行通信以扩大 肺部注射的分辨率。这些研究将探讨有关Treg调制的新观察 ARDS分辨率期间肺泡上皮的最终目标是改善患者的预后 时间致命疾病。