GLUT1-dependent glycolysis regulates age-susceptible lung fibrosis

GLUT1依赖性糖酵解调节年龄易感性肺纤维化

• 批准号: 10223408
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10223408
• 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; 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.

项目摘要 特发性肺纤维化（IPF），一种快速进行的致命肺疾病，中位生存率小于 诊断后三年，在老龄化的人口中更为普遍。糖酵解，葡萄糖的关键途径 代谢在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患者在纤维化区域暴露了较高的糖酵解活性，以高[18F] -2-氟-2-的代表 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 随着衰老的增强纤维化的发展，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发生。识别下游和上游 GLUT1调节纤维发生的机制是下一步。对于下游机制，我们有 表明非典型的TGFβ1信号传导可能是依赖GLUT1糖溶解的途径 有助于肺纤维化。对于上游机制，我们说明了依赖年龄的蛋白酶体 功能障碍可能是增强的GLUT1蛋白表达的基础。在此提案中，我们假设 蛋白酶体功能降低会导致GLUT1降解受损，进而激活信号传导 加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。 AIM 1将研究GLUT1的上游调节 通过遗传和 在我们的两个鼠纤维化模型中抑制UPS的药理方法（博来霉素诱导的肺损伤和 TGFβ1过表达模型）。 AIM 2将研究GLUT1依赖性的下游机制 肺中的糖酵解和纤维化发育。我们将比较在野生型中观察到的肺纤维化程度， 在博霉素和TGFβ1诱导的纤维化模型期间，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表达水平及其在患者中的生物标志物的作用 具有两个不同的IPF表型。这可能转化为有用的信息，可用于了解复杂的交互 在依赖Glut1的糖酵解和纤维化之间，并为为什么老年人提供了一个潜在的解释 更容易患纤维化肺部疾病。我们目前研究的结果可能支持 基于靶向GLUT1和/或其上游/下游调节器的IPF疗法。

项目成果

Role of Cholesterol 25-Hydroxylase (Ch25h) in Mediating Innate Immune Responses to Streptococcus pneumoniae Infection.

• DOI: 10.3390/cells12040570
• 发表时间: 2023-02-10
• 期刊: Cells
• 影响因子: 6

Aging and Lung Disease.

• DOI: 10.1146/annurev-physiol-021119-034610
• 发表时间: 2020-02-10
• 期刊: Annual review of physiology
• 影响因子: 18.2
• 作者: Cho SJ;Stout-Delgado HW
• 通讯作者: Stout-Delgado HW

Early growth response gene 1-mediated apoptosis is essential for transforming growth factor beta1-induced pulmonary fibrosis.

• DOI: 10.1084/jem.20040104
• 发表时间: 2004-08-02
• 期刊: JOURNAL OF EXPERIMENTAL MEDICINE
• 影响因子: 15.3
• 作者: Lee, CG;Cho, SJ;Kang, MJ;Chapoval, SR;Lee, PJ;Noble, PW;Yehualaeshet, T;Lu, BF;Flavell, RA;Milbrandt, J;Homer, RJ;Elias, JA
• 通讯作者: Elias, JA

Integrative metabolomic and proteomic signatures define clinical outcomes in severe COVID-19.

• DOI: 10.1016/j.isci.2022.104612
• 发表时间: 2022-07-15
• 期刊: ISCIENCE
• 影响因子: 5.8
• 作者: Buyukozkan, Mustafa;Alvarez-Mulett, Sergio;Racanelli, Alexandra C.;Schmidt, Frank;Batra, Richa;Hoffman, Katherine L.;Sarwath, Hina;Engelke, Rudolf;Gomez-Escobar, Luis;Simmons, Will;Benedetti, Elisa;Chetnik, Kelsey;Zhang, Guoan;Schenck, Edward;Suhre, Karsten;Choi, Justin J.;Zhao, Zhen;Racine-Brzostek, Sabrina;Yang, He S.;Choi, Mary E.;Choi, Augustine M. K.;Choo, Soo Jung;Krumsiek, Jan
• 通讯作者: Krumsiek, Jan

Decreased IDO1-dependent tryptophan metabolism in aged lung during influenza.

• DOI: 10.1183/13993003.00443-2020
• 发表时间: 2021-05
• 期刊: The European respiratory journal
• 作者: Cho SJ;Hong KS;Schenck E;Lee S;Harris R;Yang J;Choi AMK;Stout-Delgado H
• 通讯作者: Stout-Delgado H