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，治疗后的预期寿命为2-6年。 诊断.尽管进行了数十年的广泛研究，但IPF的有效治疗方法非常有限。 迫切需要在更好地理解肿瘤的基础上发现新的治疗策略。 发病机理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- 这是一个刚刚开始被人理解的概念。核心代谢途径的描述 在不同的肺细胞类型中，特别是在表观遗传水平上由特定的miRNA特异性调节， 它们如何促进受影响细胞的促纤维化表型改变，以及代谢如何 中间体在细胞间通讯中发挥作用，促进肺细胞功能障碍，将显着 提高我们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，表观遗传 和药理学方法来微调肺中失调的核心代谢程序， 深入了解核心代谢异常对肺纤维化发病机制的贡献，并确定 最好的策略来修复这些代谢畸变来治疗这种疾病。我相信我的计划将奠定一个 为设计有效肺纤维化的潜在地面制动代谢方法奠定坚实基础 治疗我的计划也将为许多其他机制相关的疾病机制提供新的见解 肺部疾病，如肺动脉高压和COPD。

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.