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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.

项目总结