Targeting the Amino Acid Transporter SLC7A5 for Treatment of Pulmonary Fibrosis

项目摘要 特发性肺纤维化（IPF）对公共卫生构成巨大负担。IPF是一种快速进展的 由细胞外基质蛋白（ECM）在成纤维细胞中的异常积累引起的肺部疾病， 估计存活3-4年。需要氨基酸来提供用于增殖的关键生物量 成纤维细胞控制氨基酸转运和代谢的各种机制代表了一个关键的机会 用于药物开发和精准医疗。SLC 7A 5（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。由于亮氨酸对于 mTOR活化和异常mTOR活化是肺纤维化的标志，统称为我们的 初步发现激发了我们的新假设，即SLC 7A 5促进肌成纤维细胞分化，mTOR 激活，抗凋亡和减少线粒体DNA损伤，并靶向SLC 7A 5， 能够消除纤维化进展的多个方面，可能代表了一种有效的方法， 开发新的治疗策略以治疗纤维增生性疾病。这些问题将通过以下方式解决： 三个高度相关的具体目标。目标1.我们将定义生物学角色，代谢和分子 SLC 7A 5调节促纤维化TGF-β信号传导的机制以及SLC 7A 5是否诱导细胞凋亡 抑制SLC 7A 5“化学敏化”纤维化病灶。目标二。我们将阐明SLC 7A 5的关键作用， 线粒体健康和新陈代谢。我们将确定是否激活细胞凋亡或抑制细胞凋亡。 通过SLC 7A 5抑制mTOR损害线粒体适应性。目标3.我们将确定在体内的疗效， 在肺纤维化和衰老的治疗模型中靶向SLC 7A 5。这些具体目标的实现将 提供了关于SLC 7A 5在介导细胞凋亡中的作用的重要机制以及临床前信息。 TGF-β的纤维增殖作用和治疗肺纤维化的新治疗方法。

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.