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.

项目摘要 特发性肺纤维化（IPF）对公共卫生构成巨大负担。IPF是一种快速进展的 由细胞外基质蛋白（ECM）在成纤维细胞中的异常积累引起的肺部疾病， 估计存活3-4年。需要氨基酸来提供用于增殖的关键生物量 成纤维细胞控制氨基酸转运和代谢的各种机制代表了一个关键的机会 用于药物开发和精准医疗。SLC 7A 5（溶质载体家族7成员5）介导摄取 必需氨基酸主要是亮氨酸和谷氨酰胺流出细胞。由于亮氨酸对于 mTOR活化和异常mTOR活化是肺纤维化的标志，统称为我们的 初步发现激发了我们的新假设，即SLC 7A 5促进肌成纤维细胞分化，mTOR 通过靶向SLC 7A 5，SLC 7A 5能够消除 成纤维细胞活化的多个方面，可能代表了开发新的治疗方法的有效途径。 治疗纤维增生性疾病的策略。这些问题将由3个高度相关的具体问题来解决。 目标。目标1.我们将定义SLC 7A 5的生物学作用、代谢和分子机制， 调节促纤维化TGF-β信号传导以及是否通过抑制SLC 7A 5诱导细胞凋亡 “化学增敏”纤维化病灶。目标2.我们将详细阐明SLC 7A 5介导的线粒体DNA的作用。 控制成纤维细胞凋亡和线粒体自噬的改变。我们还将研究是否SLC 7A 5抑制 诱导线粒体自噬并抑制IPF中线粒体自噬不足情况下的肺纤维化发展。 目标3.我们将确定靶向SLC 7A 5在肺纤维化治疗模型中的体内功效， 衰老这些特定目标的完成将提供重要的机制以及临床前信息 SLC 7A 5在介导TGF-β的纤维增殖作用中的作用和一种新的治疗方法， 肺纤维化的治疗

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