Targeting the Amino Acid Transporter SLC7A5 for Treatment of 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：
10683793
负责人：
Malay Choudhury
金额：
$ 19.57万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-07 至 2024-01-16
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10683793
关键词：
Address Adult Aging Amino Acid Transporter Amino Acids Anchorage-Independent Growth Apoptosis Attenuated Automobile Driving BCL2 gene Biogenesis Biological Biomass Bleomycin Cell Proliferation Cells Cessation of life Chronic DNA Damage Data Defect Development Diagnosis Disease Essential Amino Acids Etiology Extracellular Matrix Proteins FRAP1 gene Family Fibroblasts Fibrosis Glutamine Glycolysis Health Impairment Induction of Apoptosis Interstitial Lung Diseases Leucine Lung diseases Mediating Metabolic Metabolic Pathway Metabolism Mitochondria Mitochondrial DNA Modeling Molecular Mus Myofibroblast Neutral Amino Acids Pathogenesis Patient-Focused Outcomes Pharmacology Phenotype Predisposition Process Production Proliferating Protein Biosynthesis Proteins Public Health Pulmonary Fibrosis Recovery Regulation Resistance Resolution Respiratory Failure Role Signal Pathway Signal Transduction Therapeutic Toxic effect Transforming Growth Factor beta aged amino acid metabolism base c-myc Genes cell growth cell motility cellular targeting chemosensitizing agent 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 mitochondrial fitness mitochondrial metabolism mouse model new therapeutic target novel novel therapeutic intervention 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 resistance and reduce mitochondrial DNA damage, and by targeting SLC7A5 which could capable of abrogating multiple facet of fibrosis progression, 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 the critical role of SLC7A5 in mitochondrial fitness and metabolism. We will determine whether activation of apoptosis or suppression of mTOR by SLC7A5 inhibition impairs mitochondrial fitness. 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，凋亡耐药性并降低线粒体DNA损伤，并通过靶向SLC7A5 能够废除纤维化进展的多个方面，可能代表了一种有效的方法制定新的治疗策略来治疗纤维增生性疾病。这些问题将由 3个高度相互关联的特定目标。目标1。我们将定义生物学作用，代谢和分子 SLC7A5调节纤维化TGF-β信号的机制以及是否诱导凋亡诱导抑制SLC7A5“化学敏化”纤维化灶。目标2。我们将阐明SLC7A5在线粒体健身和代谢。我们将确定凋亡的激活或抑制是 SLC7A5抑制作用MTOR会损害线粒体适应性。目标3。我们将确定体内效率在肺纤维化和衰老的治疗模型中靶向SLC7A5。这些特定目标的完成将提供有关SLC7A5在介导的作用的重要机制和临床前信息 TGF-β的纤维增生作用和一种用于治疗肺纤维化的新治疗方法。