Mentoring in Translational Research in Interstitial Lung Diseases

项目摘要 此次续展申请以患者为中心的职业生涯中期研究人员奖的总体目标是 为了使候选人能够继续扩大她对结节病患者的研究和指导计划- 以研究为导向。这一奖项将允许她继续将大量受保护的时间投入到专业人士身上 发展她目前的辅导者，重点是成功地过渡到科学独立。在.期间 在之前的获奖期，候选人和她的受训者确定了程序性死亡的关键作用-1/STAT3 Th17细胞中的信号通路与肺结节病的进展。现在，这个团队提供了令人信服的 初步数据表明，二甲双胍在体外可以降低结节病PD-1CD4T细胞的百分比，而且这 减少与人肺成纤维细胞(HLF)胶原生成减少有关。在这次更新中 申请，德雷克博士和她的受试者将评估口服二甲双胍改变PD-1表达的能力 结节病在体内的CD4T细胞，以及确定发生这种情况的相关机制。团队将会 测定口服二甲双胍对结节病用力肺活量的影响，重点观察Th17细胞免疫功能。 代谢改变，以及STAT3信号的改变。两个具体目标如下：1) 评价口服二甲双胍降低结节病患者PD-1 CD4T细胞的体内疗效及其临床意义 对结节病FVC的影响；2)评估口服二甲双胍是否有能力减少HLF胶原的产生 在结节病研究对象中。这些转译研究将为未来的高级临床奠定坚实的基础 二甲双胍对肺结节病进展的疗效观察。建议的结果 临床和机械研究将转化为先进的临床试验，从而提供未来 为学员的职业发展提供基础、翻译和临床平台。

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.