Program on cellular metabolism and lung fibrosis

摘要 特发性肺纤维化(IPF)是一种临床难治性疾病，其预期寿命为2-6年。 诊断。尽管几十年来进行了广泛的研究，但有效的治疗IPF的方法有限，令人失望。 迫切需要在更好地了解人类免疫缺陷的基础上发现新的治疗策略。 疾病发病机制。这个项目是基于我以前的工作和愿景，肺纤维化的特点是 不同类型的肺细胞中不同核心代谢程序的扰动，一个潜在的范例- 刚刚开始受到重视的观念转变。描述核心代谢途径是如何 在不同类型的肺细胞中，特别是在表观遗传水平上受特定miRNAs调控， 它们如何促进受影响细胞的促纤维化表型改变，以及如何代谢 中介作用于细胞间的通讯将显著促进肺细胞功能障碍 提高对肺纤维化发病机制的认识。在这个节目中，我们将使用遗传学、表观遗传学 以及微调肺部失调核心代谢程序的药理学方法，以获得新的 深入了解核心代谢异常在肺纤维化发病机制中的作用并确定 治疗这种疾病的修复这些代谢异常的最佳策略。我相信我的计划将为 为设计有效治疗肺纤维化的潜在刹车代谢方法奠定坚实基础 治疗。我的程序还将为许多其他与机械相关的疾病机制提供新的线索 肺部疾病，如肺动脉高压和慢性阻塞性肺病。

Abstract Idiopathic pulmonary fibrosis (IPF) is a clinically refractory disease with a life expectancy of 2-6 years after diagnosis. Despite decades of extensive research, effective treatments for IPF are disappointingly limited. There is a pressing need for discovering novel therapeutic strategies based on better understanding of the disease pathogenesis. This program is based on my prior work and vision that lung fibrosis is characterized by perturbations of distinct core metabolic programs in different types of pulmonary cells, a potentially paradigm- shifting concept that has just begun to be appreciated. Delineation of how core metabolic pathways are specifically regulated, particularly at the epigenetic level by specific miRNAs, in different pulmonary cell types, how they contribute to the pro-fibrotic phenotypic alterations of the affected cells, and how metabolic intermediators act in intercellular communication to promoter pulmonary cell dysfunction will significantly advance our understanding of the pathogenesis of lung fibrosis. In this program, we will use genetic, epigenetic and pharmacological approaches to fine-tune dysregulated core metabolic program in the lung to gain novel insight into the contributions of core metabolic abnormalities to lung fibrosis pathogenesis and to determine the best strategies to fix these metabolic aberrations for treating this disease. I believe that my program will lay a solid foundation for designing potentially ground-braking metabolic approaches to effective lung fibrosis therapies. My program will also shed new light into disease mechanism of many other mechanistically related pulmonary disorders, such as pulmonary hypertension and COPD.