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.

Public Health Relevance

Description The program is built around my vision that pulmonary metabolic dysregulation has an important role in the pathogenesis of lung fibrosis. The studies proposed in this program should not only improve understanding of the participation of metabolic abnormalities of different types of pulmonary cells in progression of lung fibrosis, but also are likely to provide solid groundwork for translating metabolic approaches into effective lung fibrosis therapies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Unknown (R35)
Project #
1R35HL135830-01
Application #
9244521
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Harabin, Andrea L
Project Start
2017-01-03
Project End
2023-12-31
Budget Start
2017-01-03
Budget End
2017-12-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Jiang, Chunsun; Liu, Gang; Luckhardt, Tracy et al. (2017) Serpine 1 induces alveolar type II cell senescence through activating p53-p21-Rb pathway in fibrotic lung disease. Aging Cell 16:1114-1124
Xie, Na; Cui, Huachun; Ge, Jing et al. (2017) Metabolic characterization and RNA profiling reveal glycolytic dependence of profibrotic phenotype of alveolar macrophages in lung fibrosis. Am J Physiol Lung Cell Mol Physiol 313:L834-L844
Ge, Jing; Cui, Huachun; Xie, Na et al. (2017) Glutaminolysis Promotes Collagen Translation and Stability via ?-ketoglutarate Mediated mTOR Activation and Proline Hydroxylation. Am J Respir Cell Mol Biol :
Cui, Huachun; Ge, Jing; Xie, Na et al. (2017) miR-34a promotes fibrosis in aged lungs by inducing alveolarepithelial dysfunctions. Am J Physiol Lung Cell Mol Physiol 312:L415-L424
Cui, Huachun; Ge, Jing; Xie, Na et al. (2017) miR-34a Inhibits Lung Fibrosis by Inducing Lung Fibroblast Senescence. Am J Respir Cell Mol Biol 56:168-178