Targeting the Amino Acid Transporter SLC7A5 for Pulmonary Fibrosis

靶向氨基酸转运蛋白 SLC7A5 治疗肺纤维化

• 批准号: 10630480
• 负责人: Malay Choudhury
• 金额: $ 50.1万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10630480
• 关键词: Address; Adult; Aging; Amino Acid Transporter; Amino Acids; Anchorage-Independent Growth; Apoptosis; Apoptotic; Attenuated; Automobile Driving; BCL2 gene; Biogenesis; Biological; Biomass; Bleomycin; Cell Proliferation; Cells; Cessation of life; Chemosensitization; Chronic; Data; Defect; Development; Diagnosis; Disease; Essential Amino Acids; Etiology; Extracellular Matrix Proteins; FRAP1 gene; Family; Feedback; Fibroblasts; Fibrosis; Glutamine; Glycolysis; Impairment; Induction of Apoptosis; Inhibition of Apoptosis; Interstitial Lung Diseases; Leucine; Lung diseases; Mediating; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Modeling; Molecular; Mus; Myofibroblast; Neutral Amino Acids; Pathogenesis; Patient-Focused Outcomes; Phenotype; Predisposition; Process; Production; Proliferating; Protein Biosynthesis; Proteins; Public Health; Pulmonary Fibrosis; Recovery; Regulation; Resistance; Resolution; Respiratory Failure; Role; Signal Transduction; Therapeutic; Toxic effect; Transforming Growth Factor beta; aged; amino acid metabolism; c-myc Genes; cell growth; cell motility; cellular targeting; conditional knockout; cytokine; drug development; effective therapy; fibrotic lung; human very old age (85+); idiopathic pulmonary fibrosis; improved; in vivo; indium-bleomycin; inhibitor; lung repair; member; mouse model; new therapeutic target; novel; novel therapeutic intervention; pharmacologic; pre-clinical; precision medicine; pulmonary function; response; solute; targeted treatment; treatment strategy; uptake

PROJECT SUMMARY Idiopathic Pulmonary Fibrosis (IPF) constitutes a tremendous burden to public health. IPF is a rapidly progressive lung disease that results from the aberrant accumulation of extracellular matrix proteins (ECM) in fibroblasts with an estimated survival of 3-4 years. Amino acids are required to provide the critical biomass for proliferating fibroblasts. The varied mechanisms controlling amino acid transport and metabolism represent a key opportunity for drug development and precision medicine. SLC7A5 (Solute Carrier Family 7 Member 5) mediates the uptake of essential amino acids primarily leucine and efflux glutamine out of the cell. As leucine is critical for the activation of mTOR and aberrant mTOR activation is a hallmark of pulmonary fibrosis, collectively our preliminary findings motivate our novel hypothesis that SLC7A5 promotes myofibroblast differentiation, mTOR activation, apoptosis and mitophagy resistance and by targeting SLC7A5 which could capable of abrogating multiple facet of fibroblast activation, may represent a efficacious approach towards developing new therapeutic strategies to treat fibroproliferative diseases. These questions will be addressed by 3 highly interrelated Specific Aims. Aim 1. We will define the biological roles, metabolic and molecular mechanism(s) by which SLC7A5 regulate profibrotic TGF-β signaling and whether the induction of apoptosis by inhibiting SLC7A5 “chemosensitize” fibrotic foci. Aim 2. We will elucidate detailed role(s) of SLC7A5 mediated mitochondrial alteration in controlling fibroblast apoptosis and mitophagy. We will also investigate whether SLC7A5 inhibition induces mitophagy and inhibits lung fibrosis development in the setting of insufficient mitophagy as seen in IPF. Aim 3. We will determine the in vivo efficacy of targeting SLC7A5 in a therapeutic model of lung fibrosis and aging. The completion of these specific aims will provide important mechanistic as well as preclinical information on the role(s) of SLC7A5 in mediating the fibroproliferative actions of TGF-β and a new therapeutic approach for the treatment of pulmonary fibrosis.

项目总结

项目成果

Targeting Pulmonary Fibrosis by SLC1A5-Dependent Glutamine Transport Blockade.

通过 SLC1A5 依赖性谷氨酰胺转运阻断来治疗肺纤维化。

• DOI: 10.1165/rcmb.2022-0339oc
• 发表时间: 2023
• 期刊: American journal of respiratory cell and molecular biology
• 影响因子: 6.4
• 作者: Choudhury,Malay;Schaefbauer,KyleJ;Kottom,TheodoreJ;Yi,EunheeS;Tschumperlin,DanielJ;Limper,AndrewH
• 通讯作者: Limper,AndrewH