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.

项目概要 特发性肺纤维化（IPF）给公众健康带来巨大负担。 IPF是一种快速进展的疾病 由成纤维细胞中细胞外基质蛋白 (ECM) 异常积累引起的肺部疾病 预计生存期为 3-4 年。需要氨基酸来提供增殖的关键生物量 成纤维细胞。控制氨基酸转运和代谢的不同机制代表了一个关键的机会 用于药物开发和精准医学。 SLC7A5（溶质载体家族 7 成员 5）介导吸收 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 的激活和异常的 mTOR 激活是肺纤维化的标志，统称为肺纤维化。 初步研究结果激发了我们的新假设：SLC7A5 促进肌成纤维细胞分化，mTOR 激活、细胞凋亡和线粒体自噬抵抗，通过靶向 SLC7A5 可以消除 成纤维细胞激活的多个方面，可能代表开发新治疗方法的有效方法 治疗纤维增生性疾病的策略。这些问题将通过 3 个高度相关的具体问题来解决 目标。目标 1. 我们将定义 SLC7A5 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 SLC7A5 诱导细胞凋亡 “化学增敏”纤维化病灶。目标 2. 我们将阐明 SLC7A5 介导的线粒体的详细作用 控制成纤维细胞凋亡和线粒体自噬的改变。我们还将研究 SLC7A5 抑制是否 在 IPF 中线粒体自噬不足的情况下，诱导线粒体自噬并抑制肺纤维化的发展。 目标 3. 我们将确定在肺纤维化治疗模型中靶向 SLC7A5 的体内功效 老化。这些具体目标的完成将提供重要的机制以及临床前信息 关于 SLC7A5 在介导 TGF-β 纤维增殖作用中的作用以及一种新的治疗方法 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