Accession Number : AD1012229


Title :   Glucocorticoid Receptor-Mediated Repression of Pro-Inflammatory Genes in Rheumatoid Arthritis


Descriptive Note : Technical Report,20 Sep 2014,19 Sep 2015


Corporate Author : Hospital For Special Surgery Fund New York United States


Personal Author(s) : Rogatsky,Inez


Full Text : http://www.dtic.mil/dtic/tr/fulltext/u2/1012229.pdf


Report Date : 01 Oct 2015


Pagination or Media Count : 41


Abstract : Most rheumatoid arthritis (RA) patients rely on glucocorticoids (GCs) at some point during the disease. GCs signal through the GC receptor(GR), a transcription factor that in addition to binding DNA directly can tether to DNA-bound AP1 and NFkB and repress their numerous pro-inflammatory target genes. We discovered that GR-Interacting Protein (GRIP)1 in macrophages (M) serves as a novel GR corepressor. Notably, GR:GRIP1 complexes repress pro-inflammatory genes of two classes: those activated through RNA polymerase(Pol)II recruitment and transcription initiation; and others, pre-loaded with paused Pol II that requires a signal for entry into productive elongation. We aim to dissect the role of M GRIP1 as a driver of anti-inflammatory actions of GCs at the level of GR transcription complexes at genes of each regulatory class and in mouse models of RA. Having established technologies to identify GR:GRIP1-regulatedgenes in M genome-wide, we are creating cistromes of where GR, GRIP1 and Pol II bind in inflammatory and GC-treated M. We have made a substantial progress in understanding mechanistically how GR:GRIP1 repress pro-inflammatory genes of different classes. Using representative genes of each class, we are able to dissect the differences in step-wise assembly of the activation complexes that become targets for GR repression.


Descriptors :   arthritis , Joints(Anatomy) , transcription factors , inflammation , targets , Autoimmune diseases , macrophages , cytokines


Distribution Statement : APPROVED FOR PUBLIC RELEASE