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.

项目总结

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.

早期生长反应基因1介导的凋亡对于转化生长因子beta1诱导的肺纤维化至关重要。

• 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

Impact of Senolytic Treatment on Gene Expression in Aged Lung.

• DOI: 10.3390/ijms24087628
• 发表时间: 2023-04-21
• 期刊: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
• 影响因子: 5.6
• 作者: Cho, Soo Jung;Pronko, Alexander;Yang, Jianjun;Stout-Delgado, Heather
• 通讯作者: Stout-Delgado, Heather