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

基本信息

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
项目类别：
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

项目摘要

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）构成了公共卫生的巨大伯宁。 IPF是一个快速进步的肺部疾病是由于成纤维细胞中细胞外基质蛋白（ECM）异常积累而引起的估计生存率为3 - 4年。需要氨基酸提供临界生物量以增殖成纤维细胞。控制氨基酸传输和代谢的多种机制代表了一个关键机会用于药物开发和精确医学。 SLC7A5（Solute Carrier家族7成员5）介导吸收必需氨基酸的原代亮氨酸和外排谷氨酰胺从细胞中脱出。因为亮氨酸对 MTOR和异常MTOR激活的激活是肺纤维化的标志，共同初步发现动机我们的新型假设SLC7A5促进了肌纤维细胞分化，mtor 激活，凋亡和线粒体耐药性，并通过靶向能够废除的SLC7A5 成纤维细胞激活的多个方面可能代表开发新治疗的有效方法治疗纤维增生性疾病的策略。这些问题将由3个高度相互关联的特定来解决目标。 AIM 1。我们将定义SLC7A5的生物学作用，代谢和分子机制调节纤维化的TGF-β信号传导以及是否通过抑制SLC7A5诱导凋亡 “化学敏化”纤维化灶。 AIM 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的改变。我们还将研究SLC7A5是否抑制如IPF所见，在线粒体不足的情况下，诱导线粒体并抑制肺纤维化的发展。 AIM 3。我们将在肺纤维化治疗模型中确定靶向SLC7A5的体内效率老化。这些特定目标的完成将提供重要的机械和临床前信息关于SLC7A5在介导TGF-β的纤维增生作用和一种新的治疗方法中的作用肺纤维化的治疗。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

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