Mentoring in Translational Research in Interstitial Lung Diseases

间质性肺疾病转化研究的指导

基本信息

批准号：
10812018
负责人：
Wonder P. Drake
金额：
$ 11.4万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-15 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10812018
关键词：
Address Award Basic Science Blinded CD4 Positive T Lymphocytes Cells Clinical Clinical Research Clinical Trials Coculture Techniques Collaborations Collagen Data Development Disease Disparity Fibroblasts Foundations Future Genes Goals Granulomatous Granulomatous disease Health Human IL17 gene In Vitro Inflammation Interstitial Lung Diseases Investigation Lung Mass Spectrum Analysis Mentors Metabolic Pathway Metformin Microarray Analysis Midcareer Investigator Award in Patient-Oriented Research Nuclear Magnetic Resonance Oral Outcome Pathogenesis Patients Peripheral Blood Mononuclear Cell Phase Placebos Production Pulmonary Fibrosis Pulmonary Sarcoidosis Randomized Receptor Signaling Reporting Research Research Personnel Role STAT3 gene Sarcoidosis Serum Signal Pathway Signal Transduction Stat3 Signaling Pathway Susceptibility Gene T-Cell Receptor T-Lymphocyte Testing Therapeutic Time Translating Translational Research Vital capacity career development clinical investigation clinically significant cytokine effector T cell experience experimental study genome wide association study immunoregulation improved in vivo metabolome metabolomics next generation novel patient oriented research programmed cell death protein 1 programs prospective pulmonary function receptor therapy development

项目摘要

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.

项目概要此次续签以患者为导向的研究中职业生涯研究者奖的总体目标是使候选人能够继续扩大她在结节病患者方面的研究和指导计划导向研究。该奖项将使她能够继续将大量受保护的时间投入到专业领域她目前的学员的发展重点是成功过渡到科学独立。期间在之前的颁奖期间，候选人和她的学员确定了 Programmed Death-1/STAT3 的关键作用 Th17 细胞与肺结节病进展的信号通路。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+CD4+ T 细胞的百分比，并且这减少与人肺成纤维细胞（HLF）胶原蛋白生成减少有关。在这次更新中 Drake 博士和她的学员将评估口服二甲双胍改变 PD-1 表达的能力体内结节病 CD4+ T 细胞，并确定其发生的相关机制。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 Th17 细胞免疫代谢组学的改变，以及 STAT3 信号传导的改变。两个具体目标如下： 1）评估口服二甲双胍对结节病受试者 PD-1+CD4+T 细胞减少的体内疗效及其影响对结节病 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受试者中。这些转化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疗效的研究。拟议的结果临床和机制研究将转化为高级临床试验，从而为未来提供为学员的职业发展提供基础、转化和临床平台。