Idiopathic pulmonary fibrosis (IPF) is an age related fatal disease with unknown etiology. Its incidence increases with age, environmental effects is important. Epigenetic changes, including DNA methylation and histone modifications, are major causes of age-related diseases. Environmental stressors and aging contribute to histone modifications. Epigenetic modifications are potentially reversible. We and others have established that epigenetic mechanisms participate in the pathogenesis of IPF. Aging may potentiate the susceptibility to environmental stress by modulating pro-fibrotic cellular phenotypes in IPF. However, studies of epigenetic regulation, in particular histone modifications and their related cellular phenotypes in the aging lung and in IPF are lacking. Chromatin structure, which is affected by histone modifications, is an important determinant of the cell phenotype. The active histone mark H4K16Ac epigenetically regulates gene expression. Our preliminary data demonstrated the dysregulation of this histone modification in IPF fibroblasts. We hypothesize that age-related histone modifications, in particular H4K16Ac, mediates fibrotic cell phenotype, promotes senescence and induced apoptosis resistant lung fibroblasts that leads to persistent fibrosis in aging. Targeting this histone modification will alter pro-fibrotic ell phenotypes and promote resolution of fibrosis.
Our specific aims are: (1) Determine mechanisms that regulate H4K16Ac in persistent lung fibrosis associated with aging. (2) Determine the role of H4K16Ac in regulating pro-fibrotic phenotypes in fibrotic lung fibroblasts. (3) Determine the efficacy of targeting H416Ac in an aging mouse model of persistent lung fibrosis. The proposed studies will define the role of age-related histone modification H4K16Ac in the pathogenesis of IPF, and translate that knowledge to novel therapeutic interventions for pulmonary fibrosis.

Public Health Relevance

Idiopathic Pulmonary Fibrosis (IPF) is an age related fatal disease with unknown pathogenesis and associated with high mortality. This project will examine age-related histone modification and its effects on various cellular functions in primary fibroblasts from murine model of lung fibrosis of young and aged mice as well as from IPF and age-matched control samples. This study will evaluate the efficacy of modulating specific histone modification to be used as a therapeutic method for IPF; the completion of this study will further our understanding of this deadly disease and uncover novel therapeutic molecular targets

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG050567-01A1
Application #
9106244
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Macchiarini, Francesca
Project Start
2016-06-01
Project End
2021-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
1
Fiscal Year
2016
Total Cost
$295,844
Indirect Cost
$90,844
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
Zhang, Xiangyu; Hu, Min; Lyu, Xing et al. (2017) DNA methylation regulated gene expression in organ fibrosis. Biochim Biophys Acta 1863:2389-2397