Regulatory T Cells Promote Alveolar Epithelial Repair

项目摘要 本次K08临床科学家导师职业奖申请的全球目标是促进发展 基本技能，这些技能将使候选人成为一名学术内科医生-科学家。该提案提供了 不仅是新技术，更重要的是理解 关于它们在患者护理中的适用性的观察和想法。候选人，他的 Mentor和他的顾问委员会设计了一个培训计划，其中包括严格的研究部分 以及建立成功职业所必需的思维过程和原则的教学指导 发展。通过课程学习和实践经验，应聘者将加深理解 肺损伤发生和解决的复杂免疫机制。他的临床工作 在医疗重症监护室照顾严重肺部疾病的患者将成为他的基础研究 并指导将这项工作转化为病人护理工作。急性呼吸窘迫综合征 (ARDS)的特点是低氧血症、毛细血管渗漏、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)；然而，已发表的研究表明Foxp3+调节性T细胞(Treg)在 实验性ALI的解决方案。此外，ARDS患者的支气管肺泡液中Tregs增加， 这表明它们在人类对肺损伤的免疫反应中很重要。在急性或慢性损伤中 肺上皮再生失败在ALI、肺炎、肺损伤等过程中起一定作用。 纤维化、癌症、慢性阻塞性肺病和衰老。最近，人们对涉及到的细胞类型有了相当大的兴趣 修复和调节这一过程。候选人的数据表明，特雷格的存在增强了 肺泡上皮修复，这是一个以前没有描述过的新发现。这份提案审查了特雷格 在ALI消退过程中对肺泡上皮细胞的影响，希望确定新的机制，可能 为ARDS患者带来了潜在的治疗选择。特定的靶点利用体内和体外两种方法 研究树突状细胞与肺泡上皮相互作用的技术。目的1研究CD103的作用 TREG在ALI消退中的表达及CD103通过滞留促进上皮修复的假说 Tregs在上皮部位的炎症和增强其组织修复作用。目标2决定了影响 在ALI决议中Treg表达的KGF，假设该KGF促进上皮动力学，表面活性物质 表达，和障碍的完整性。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通讯，以放大 肺部炎症消退。这些研究将探索关于Treg调制的新观察。 ARDS缓解期间的肺泡上皮细胞，最终目标是改善这种情况下的患者预后 有时是致命的疾病。

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.