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.

项目概要特发性肺纤维化（IPF）是一种快速进展的疾病，给公众健康带来巨大负担。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估计需要氨基酸存活 3-4 年才能提供增殖的关键生物量。成纤维细胞控制酸转运和代谢的不同机制代表了一个关键机会。用于药物开发和精准医学。SLC7A5（溶质载体家族 7 成员 5）介导摄取。必需氨基酸主要是亮氨酸和谷氨酰胺流出细胞，因为亮氨酸对于细胞至关重要。 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、细胞凋亡抵抗并减少线粒体 DNA 损伤，并且通过靶向 SLC7A5，可以能够消除纤维化进展的多个方面，可能代表一种有效的方法开发新的治疗策略来治疗纤维增生性疾病将得到解决。 3 个高度相关的具体目标 1. 我们将定义生物学作用、代谢作用和分子作用。 SLC7A5 调节促纤维化 TGF-β 信号传导的机制以及是否通过诱导细胞凋亡抑制SLC7A5“化学增敏”纤维化病灶。目标2。我们将阐明SLC7A5在纤维化病灶中的关键作用。我们将确定是否激活细胞凋亡或抑制线粒体。 SLC7A5 抑制 mTOR 会损害线粒体健康。目标 3。我们将确定其体内功效。在肺纤维化和衰老的治疗模型中靶向SLC7A5将完成这些特定目标。提供重要的机械信息以及有关 SLC7A5 在介导 TGF-β的纤维增殖作用和治疗肺纤维化的新方法。