GLUT1-dependent glycolysis regulates age-susceptible lung fibrosis

项目总结 特发性肺纤维化(IPF)是一种进展迅速、致命的肺部疾病，中位生存期不到 确诊后三年，在老龄化人口中更为普遍。糖酵解--葡萄糖的关键途径 代谢在调节宿主对纤维化肺损伤的反应性中起着重要作用。最新研究 据报道，IPF患者在纤维化区域表现出较高的糖酵解活性，表现为高[18F]-2-氟-2- 正电子发射断层扫描中的脱氧葡萄糖摄取。我们已经证明了 纤维化的发展随着年龄的增长而增强，并依赖于葡萄糖转运蛋白1(GLUT1) 糖酵解有助于促进老年肺纤维化的形成。确定下行和上行 GLUT1调节纤维化形成的机制是下一步必不可少的。对于下游机制，我们有 研究表明，非典型的转化生长因子β-1信号可能是GLUT1依赖的糖酵解的途径 会导致肺纤维化。对于上游机制，我们已经说明了年龄依赖的蛋白酶体 功能障碍可能是GLUT1蛋白表达增强的原因。在这个提案中，我们假设 蛋白酶体功能下降导致GLUT1降解受损，GLUT1进而激活信号 增强或调节下游细胞反应的途径，从而有助于增加GLUT1- 老年肺糖酵解和纤维化的相关性研究。目标1将研究GLUT1的上游调控 泛素-蛋白酶体系统(UPS)的表达与年龄相关性肺纤维化 在我们的两个小鼠纤维化模型中抑制UPS的药理学方法(博莱霉素诱导的肺损伤和 转化生长因子β-1过表达模型)。目标2将研究GLUT1依赖的下游机制 糖酵解和肺纤维化的发展。我们将比较野生型中观察到的肺纤维化程度， 在博莱霉素和转化生长因子β1诱导的纤维化模型中，Glut1基因敲除和Glut1过表达的小鼠。目标 3将使用人类IPF队列来确定患者GLUT1的表达水平及其作为生物标记物的作用 有两种不同的IPF表型。这可能会转化为有助于理解复杂相互作用的信息 GLUT1依赖的糖酵解和纤维化之间的关系，并为为什么老年人 更容易患上纤维性肺病。我们目前的研究结果可能会支持 基于靶向GLUT1和/或其上游/下游调节因子的IPF治疗。

PROJECT SUMMARY Idiopathic pulmonary fibrosis (IPF), a rapidly progressive, fatal lung disease with a median survival of less than three years post diagnosis, is more prevalent in aging population. Glycolysis, a critical pathway in glucose metabolism plays an important role in regulating host responsiveness to fibrotic lung injury. Recent studies reported that IPF patients exhibit higher glycolytic activity in fibrotic areas represented by high [18F]-2-fluoro-2- deoxyglucose (FDG) uptake in positron emission tomography (PET) scanning. We have demonstrated that fibrosis development is enhanced with aging and that increased glucose transporter 1 (GLUT1)-dependent glycolysis contributes to enhanced fibrogenesis in aged lung. Identifying the downstream and upstream mechanism by which GLUT1 regulates fibrogenesis is essential next step. For downstream mechanism we have shown that non-canonical TGFβ1 signaling may be the pathway by which GLUT1-dependent glycolysis contributes to lung fibrosis. For upstream mechanism we have illustrated that age-dependent proteasome dysfunction might underlie enhanced GLUT1 protein expression. In this proposal we hypothesized that decreased proteasome function contributes to impaired GLUT1 degradation, which in turn activates signaling pathways to reinforce or modulate downstream cellular responses and thereby contribute to increased GLUT1- dependent glycolysis and fibrogenesis in aged lung. Aim 1 will investigate the upstream regulation of GLUT1 expression and age-dependent lung fibrosis by the ubiquitin-proteasome system (UPS) by using genetic and pharmacologic approaches to inhibit UPS in our two murine fibrosis models (bleomycin-induced lung injury and TGFβ1 overexpression model). Aim 2 will investigate the downstream mechanism of GLUT1-dependent glycolysis and fibrosis development in lung. We will compare the extent of lung fibrosis observed in wild type, GLUT1 knockout, and GLUT1 overexpressing mice during bleomycin- and TGFβ1-induced fibrosis models. Aim 3 will use human IPF cohort to define the levels of GLUT1 expression and their roles as a biomarker in patients with two distinct IPF phenotypes. This may translate into information useful to understand the complex interaction between GLUT1-dependent glycolysis and fibrosis, and provide a potential explanation for why older people are more susceptible to fibrotic lung disease. Results from our current studies may support the development of therapies for IPF based on targeting GLUT1 and/or its upstream/downstream regulators.