Sarcoidosis is a granulomatous disease of unknown etiology that results in significant morbidity and mortality, primarily from respiratory failure. Wile this disease results from a gene-environment interaction, in which environmental exposure(s) in a genetically susceptible host results in Th1 immune-mediated response to an unknown antigen, the environmental impacts, genetic factors, genes and pathways involved in sarcoidosis are largely unknown. The goal of this study is to define the epigenetic alterations (histone modifications) in bronchoalveolar CD4+ T-cells, which in turn impact gene expression and CD4+ T-cell differentiation and activation, which contribute to sarcoidosis pathology. Our proposal is unique as we are focusing on specific epigenetic histone modifications, which are known to mediate environmental regulation of CD4+ T cell differentiation and function. We propose three aims to address our hypothesis that epigenetic modifications regulate bronchoalveolar CD4+ Th1 vs. T-regulatory cell gene expression profiles and T cell activity, thus affecting sarcoidosis pathogenesis which ultimately controls the variable course of disease observed in sarcoidosis. Using a novel approach that has not been undertaken in sarcoidosis but proven in other inflammatory pulmonary and non-pulmonary disorders, in Aim 1 we will determine the genome-wide pattern of epigenetic histone modifications specific for BAL CD4+ T cell skewing and activity in sarcoidosis via Chromatin Immuno-Precipitation coupled with next generation sequencing (ChIP-seq). We will examine both permissive and repressive histone modifications known to regulate T cell differentiation and activity in two distinct pulmonary sarcoidosis groups, active/progressive disease and inactive/remitting disease.
In Aim 2, the transcriptome of BAL CD4+ T cells will be analyzed via next-gen sequencing RNA-seq. This transcriptome will be computationally integrated with the histone signature from ChIP-seq to generate an epigenetically regulated sarcoidosis gene expression profile in BAL CD4+ T cells. This profile can then potentially be used as a diagnostic tool.
In Aim 3, we will mechanistically test the role of these specific epigenetic mechanisms to regulate gene expression, T cell skewing and immune cell function associated with sarcoidosis via ex vivo treatment of lung CD4+ T cells with specific histone modifying enzymes and drugs. This project will elucidate the epigenetic signature of BAL CD4+ T cells in sarcoidosis patients, which will significantly enhance our understanding of the immunomodulatory mechanisms regulating sarcoidosis and provide an epigenetic map for diagnosis and potentially targeted treatment.

Public Health Relevance

Sarcoidosis is a rare disease of unknown cause that results in significant morbidity and mortality. The reason why some individuals develop this disease and others do not and why some develop more severe forms of this disease is not well understood. However, there is a growing appreciation for the role of environmental exposures and the role they play in modulating sarcoidosis disease. This proposal will define factors that may explain the diversity of sarcoidosis while also defining potential environmental disease modulation via the role epigenetic mechanisms play in sarcoidosis development. These defined factors can serve as biomarkers or predictors of disease and ultimately even targets for therapy. In this project, we begin a mechanistic examination of epigenetic regulation of some of these specific sarcoidosis disease pathways that may be targeted for future therapy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL127461-04
Application #
9610714
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Vuga, Louis J
Project Start
2016-01-01
Project End
2019-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
National Jewish Health
Department
Type
DUNS #
076443019
City
Denver
State
CO
Country
United States
Zip Code
80206