Corticosteroid hormones are important in a wide variety of biological contexts and are widely used as therapeutic agents. The most prevalent uses of corticosteroids in the clinical environment include the treatment of asthma and the prenatal administration of corticosteroids to mothers expecting to deliver babies pre-term, in order to facilitate terminal lung morphogenesis. Despite the broad clinical utility of corticosteroids, not all patients respond to their therapeutic effects. Additionally, off target efects of corticosteroids include metabolic perturbations detrimental to patient health. Our recent research suggests that several novel mechanisms govern the activity and specificity of glucocorticoid (GC) signaling. Specifically, we have demonstrated that the vast minority of glucocorticoid receptor (GR) binding sites controls the majority of GC-induced gene expression. We provide evidence for a novel enhancer-cluster model of GR-induced gene activation. In this proposal we will test our core hypothesis that GR binding at sites that contain the canonical GR binding motif drive the primary transcription response to GCs and that AP1-tethered binding sites proximal to direct GR binding sites act secondarily to modulate the primary GC-induced transcription response. Ultimately understanding the molecular underpinnings that govern the activity of the GR will yield critical insights that could increase the clinical efficacy of GCs amng GC-nonresponsive patients and reduce the off target effects of corticosteroid therapies.

Public Health Relevance

Corticosteroid hormones are important in a wide variety of biological contexts and are widely used as therapeutic agents, particularly in the treatment of pulmonary disease. Our recent research suggests that several novel mechanisms may govern the activity and specificity of corticosteroid signaling. We propose a series of hypothesis driven experiments to probe possible novel mechanisms of corticosteroid activity.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31HL129743-01
Application #
8983936
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Tigno, Xenia
Project Start
2015-09-01
Project End
2017-08-31
Budget Start
2015-09-01
Budget End
2016-08-31
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Duke University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
McDowell, Ian C; Barrera, Alejandro; D'Ippolito, Anthony M et al. (2018) Glucocorticoid receptor recruits to enhancers and drives activation by motif-directed binding. Genome Res 28:1272-1284
Lea, Amanda J; Vockley, Christopher M; Johnston, Rachel A et al. (2018) Genome-wide quantification of the effects of DNA methylation on human gene regulation. Elife 7:
Vockley, Christopher M; McDowell, Ian C; D'Ippolito, Antony M et al. (2017) A long-range flexible billboard model of gene activation. Transcription 8:261-267
Vockley, Christopher M; D'Ippolito, Anthony M; McDowell, Ian C et al. (2016) Direct GR Binding Sites Potentiate Clusters of TF Binding across the Human Genome. Cell 166:1269-1281.e19