GLUT1-dependent glycolysis regulates age-susceptible lung fibrosis

GLUT1依赖性糖酵解调节年龄敏感肺纤维化

• 批准号: 9750795
• 负责人: Soo Jung Cho
• 金额: $ 16.58万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-09 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9750795
• 关键词: 1-Phosphatidylinositol 3-Kinase; Age; Aging; Area; Attenuated; Biological Aging; Biological Markers; Bleomycin; Cell membrane; Cell physiology; Complex; Critical Pathways; Crossbreeding; Deterioration; Development; Diagnosis; Disease; Disease Progression; Down-Regulation; Exhibits; Experimental Models; Fibroblasts; Fibrosis; Functional disorder; Gene Silencing; Genetic; Glucose; Glucose Transporter; Glycolysis; Goals; Human; Impairment; In Vitro; Interstitial Lung Diseases; Knock-out; Lung; Lung diseases; MAP Kinase Gene; MG132; Mediating; Messenger RNA; Mitogen-Activated Protein Kinases; Modeling; Molecular; Morbidity - disease rate; Mus; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmacology; Phenotype; Play; Positron-Emission Tomography; Post-Translational Regulation; Process; Protein Family; Proteins; Pulmonary Fibrosis; Reporting; Respiratory physiology; Role; SLC2A1 gene; Signal Pathway; Signal Transduction; Structure of parenchyma of lung; System; Testing; Tissues; Transcriptional Regulation; Translating; Ubiquitin; age related; aged; aging population; base; blood glucose regulation; cohort; cytokine; design; fibrogenesis; fluorodeoxyglucose; genetic approach; glucose metabolism; glucose transport; idiopathic pulmonary fibrosis; improved; in vitro Model; indexing; lung injury; misfolded protein; mortality; multicatalytic endopeptidase complex; overexpression; protein expression; proteostasis; pulmonary function; response; therapy development; uptake

PROJECT SUMMARY Idiopathic pulmonary fibrosis (IPF), a rapidly progressive, fatal lung disease with a median survival of less than three years post diagnosis, is more prevalent in aging population. Glycolysis, a critical pathway in glucose metabolism plays an important role in regulating host responsiveness to fibrotic lung injury. Recent studies reported that IPF patients exhibit higher glycolytic activity in fibrotic areas represented by high [18F]-2-fluoro-2- deoxyglucose (FDG) uptake in positron emission tomography (PET) scanning. We have demonstrated that fibrosis development is enhanced with aging and that increased glucose transporter 1 (GLUT1)-dependent glycolysis contributes to enhanced fibrogenesis in aged lung. Identifying the downstream and upstream mechanism by which GLUT1 regulates fibrogenesis is essential next step. For downstream mechanism we have shown that non-canonical TGFβ1 signaling may be the pathway by which GLUT1-dependent glycolysis contributes to lung fibrosis. For upstream mechanism we have illustrated that age-dependent proteasome dysfunction might underlie enhanced GLUT1 protein expression. In this proposal we hypothesized that decreased proteasome function contributes to impaired GLUT1 degradation, which in turn activates signaling pathways to reinforce or modulate downstream cellular responses and thereby contribute to increased GLUT1- dependent glycolysis and fibrogenesis in aged lung. Aim 1 will investigate the upstream regulation of GLUT1 expression and age-dependent lung fibrosis by the ubiquitin-proteasome system (UPS) by using genetic and pharmacologic approaches to inhibit UPS in our two murine fibrosis models (bleomycin-induced lung injury and TGFβ1 overexpression model). Aim 2 will investigate the downstream mechanism of GLUT1-dependent glycolysis and fibrosis development in lung. We will compare the extent of lung fibrosis observed in wild type, GLUT1 knockout, and GLUT1 overexpressing mice during bleomycin- and TGFβ1-induced fibrosis models. Aim 3 will use human IPF cohort to define the levels of GLUT1 expression and their roles as a biomarker in patients with two distinct IPF phenotypes. This may translate into information useful to understand the complex interaction between GLUT1-dependent glycolysis and fibrosis, and provide a potential explanation for why older people are more susceptible to fibrotic lung disease. Results from our current studies may support the development of therapies for IPF based on targeting GLUT1 and/or its upstream/downstream regulators.

项目概要 特发性肺纤维化 (IPF) 是一种快速进展的致命性肺部疾病，中位生存期低于 诊断后三年，在老龄化人群中更为普遍。糖酵解，葡萄糖的关键途径 代谢在调节宿主对纤维化肺损伤的反应中起着重要作用。最近的研究 据报道，IPF 患者在纤维化区域表现出较高的糖酵解活性，以高[18F]-2-氟-2-为代表 正电子发射断层扫描 (PET) 扫描中的脱氧葡萄糖 (FDG) 摄取。我们已经证明了 纤维化的发展随着年龄的增长而增强，并且葡萄糖转运蛋白 1 (GLUT1) 依赖性增加 糖酵解有助于增强老年肺的纤维化。识别下游和上游 GLUT1 调节纤维发生的机制是下一步的关键。对于下游机制，我们有 研究表明，非经典 TGFβ1 信号传导可能是 GLUT1 依赖性糖酵解的途径 有助于肺纤维化。对于上游机制，我们已经说明了年龄依赖性蛋白酶体 功能障碍可能是 GLUT1 蛋白表达增强的基础。在这个提案中，我们假设 蛋白酶体功能下降导致 GLUT1 降解受损，进而激活信号传导 增强或调节下游细胞反应的途径，从而有助于增加 GLUT1- 老年肺中的依赖性糖酵解和纤维发生。目标1将调查GLUT1的上游调控 泛素蛋白酶体系统（UPS）通过使用遗传和年龄相关的表达和年龄依赖性肺纤维化 在我们的两个小鼠纤维化模型（博莱霉素诱导的肺损伤和 TGFβ1 过表达模型）。目标2将研究GLUT1依赖的下游机制 肺中糖酵解和纤维化的发展。我们将比较野生型中观察到的肺纤维化程度， 博莱霉素和 TGFβ1 诱导的纤维化模型中 GLUT1 敲除和 GLUT1 过表达小鼠。目的 3 将使用人类 IPF 队列来定义 GLUT1 表达水平及其作为患者生物标志物的作用 具有两种不同的 IPF 表型。这可能会转化为有助于理解复杂交互的信息 GLUT1 依赖性糖酵解和纤维化之间的关系，并为为什么老年人 更容易患纤维化肺部疾病。我们目前的研究结果可能支持开发 基于靶向 GLUT1 和/或其上游/下游调节因子的 IPF 疗法。