Mentoring in Translational Research in Interstitial Lung Diseases

项目摘要 这项以患者为导向的研究中期职业研究者奖更新申请的总体目标是 使候选人能够继续扩大她在结节病患者中的研究和指导计划- 导向研究。这一奖项将使她能够继续投入大量的保护时间的专业 发展她目前的学员，重点是成功过渡到科学独立。期间 在上一个奖励期，候选人和她的学员确定了程序化死亡-1/STAT3的关键作用 Th 17细胞信号通路与肺结节病进展的关系。现在这个团队提供了令人信服的 初步数据表明，二甲双胍在体外可降低结节病PD-1+ CD 4 + T细胞的百分比， 减少与人肺成纤维细胞（HLF）胶原蛋白产生减少有关。在这次更新中， 申请，德雷克博士和她的学员将评估口服二甲双胍改变PD-1表达的能力， 结节病的CD 4 + T细胞在体内，以及确定相关的机制，这发生。该团队将 确定口服二甲双胍对结节病用力肺活量（FVC）的影响，重点关注Th 17细胞免疫功能， 代谢组学改变以及STAT 3信号传导的改变。具体目标如下：1） 评估口服二甲双胍对结节病受试者中PD-1+ CD 4 + T细胞减少的体内疗效及其 对结节病FVC的影响; 2）评估口服二甲双胍是否能够减少HLF胶原蛋白的产生 在结节病患者中。这些转化研究将为未来先进的临床研究奠定坚实的基础。 二甲双胍对肺结节病进展有效性的研究。结果从拟议的 临床和机制研究将转化为先进的临床试验，从而提供未来的 学员为他们的职业发展提供基础、转化和临床平台。

Project Summary The overall goal of this renewal application for a MidCareer Investigator Award in Patient-Oriented Research is to enable the candidate to continue to expand her research and mentoring programs in sarcoidosis patient- oriented research. This award will allow her to continue to devote significant protected time to the professional development of her current mentees with a focus on successful transition to scientific independence. During the prior award period, the candidate and her mentees identified a crucial role for the Programmed Death-1/STAT3 signaling pathway in Th17 cells to pulmonary sarcoidosis progression. Now this team provides compelling preliminary data that metformin reduces the percentage of sarcoidosis PD-1+CD4+ T cells in vitro, and that this reduction is associated with reduced human lung fibroblast (HLF) collagen production. In this renewal application, Dr. Drake and her mentees will assess the capacity of oral metformin to alter PD-1 expression on sarcoidosis CD4+ T cells in vivo, as well as identify relevant mechanisms by which this occurs. The team will determine the impact of oral metformin on sarcoidosis forced vital capacity (FVC), focus on Th17 cell immuno- metabolomic alterations, as well as alterations in STAT3 signaling. The two specific aims are as follows: 1) To assess the in vivo efficacy of oral metformin on reduction of PD-1+CD4+ T cells in sarcoidosis subjects and its impact on sarcoidosis FVC; 2) To assess if oral metformin has the capacity to reduce HLF collagen production in sarcoidosis subjects. These translational investigations will lay a firm foundation for a future advanced clinical investigation of metformin efficacy against pulmonary sarcoidosis progression. The results from the proposed clinical and mechanistic investigations will be translated into advanced clinical trials, thus providing future mentees with basic, translational and clinical platforms for their career development.