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AHR Signaling in Mammalian and Non-Mammalian Models

Award Number: R01ES006272
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/10/1992
PERIOD OF PERFORMANCE END DATE: 08/30/2016

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AHR Signaling in Mammalian and Non-Mammalian Models - DESCRIPTION (provided by applicant): 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and polynuclear aromatic hydrocarbons are ubiquitous environmental contaminants with adverse effects on human health. These compounds cause toxicity by activating the aryl hydrocarbon receptor (AHR). The AHR also has physiological roles regulating vascular development, immune function, and cell growth, suggesting a role in human disease. To understand these diverse functions and the possible role of AHR in human disease, it is important to determine how AHR signaling is regulated. The negative regulation of AHR signaling is poorly understood. An inhibitor of AHR transcriptional activation function, AHR repressor (AHRR), has been identified, but its role in regulating AHR signaling remains enigmatic, and possible functions beyond the AHR pathway have been virtually ignored. Recent epidemiological studies have linked AHRR Pro185 and Ala185 polymorphisms to human reproductive disorders and AHRR has been identified as a likely tumor suppressor gene in humans. However, fundamental questions concerning the biochemical and functional characteristics of the AHRR and its variants remain unresolved, preventing a full understanding of its roles in human disease. The studies proposed here will utilize established vertebrate model systems (human cells and zebrafish embryos) to determine the transcription factor specificity and gene selectivity of AHRR and its polymorphic variants, the mechanism by which AHRR represses AHR and hypoxia inducible factors (HIFs), and the role of AHRR in regulating embryonic development and the response to TCDD and hypoxia in vivo. The central hypothesis is that AHRR acts through a transrepression mechanism to regulate the transcriptional activity of several transcription factors. In Aim 1, we will test the hypothesis that human AHRR can repress a variety of constitutively active and conditional transcription factors. We will also use gain-of-function (Tet-On) and loss-of- function (siRNA) experiments in human cell lines to determine the AHR and HIF target gene specificity of repression by AHRR. In Aim 2, we will use AHRR mutants, co-immunoprecipitation and chromatin immunoprecipitation assays, and ARNT-deficient cells to test several hypotheses: a) that the human AHRR and its variants act by a transrepression mechanism; b) that AHRR repression is ARNT-dependent; and c) that AHRR represses by binding to AHR and HIF or their transcription complexes. In Aim 3, we will investigate the in vivo function of AHRR in the powerful zebrafish embryo model system. We will generate germ-line null mutants for each of the two zebrafish AHRR paralogs. With these AHRR-null fish combined with AHRR overexpression experiments, we will assess the in vivo transcription factor and gene target specificity of AHRRs, the role of transrepression in the mechanism of action, and the roles of AHRR in embryonic development and the response to activators of AHR and HIF.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2017 ( Subtotal = -$26 )
2017	2014	WOODS HOLE OCEANOGRAPHIC INSTITUTION	266 WOODS HOLE RD	WOODS HOLE	MA	02543	BARNSTABLE	USA	Environmental Health	000	18	2/1/2017	NON-COMPETING CONTINUATION	-$26
														Subtotal = -$26

Issue Date FY: 2016 ( Subtotal = $0 )
2016	2014	WOODS HOLE OCEANOGRAPHIC INSTITUTE	MS # 14 CHALLENGER HOUSE	WOODS HOLE	MA	02543	BARNSTABLE	USA	Environmental Health	000	18	11/25/2015	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2014 ( Subtotal = $382,201 )
2014	2014	WOODS HOLE OCEANOGRAPHIC INSTITUTE	MS # 14 CHALLENGER HOUSE	WOODS HOLE	MA	02543	BARNSTABLE	USA	Environmental Health	001	18	4/9/2014	NON-COMPETING CONTINUATION	$34,747
2014	2014	WOODS HOLE OCEANOGRAPHIC INSTITUTE	MS # 14 CHALLENGER HOUSE	WOODS HOLE	MA	02543	BARNSTABLE	USA	Environmental Health	000	18	11/28/2013	NON-COMPETING CONTINUATION	$347,454
														Subtotal = $382,201

Issue Date FY: 2013 ( Subtotal = $372,171 )
2013	2013	WOODS HOLE OCEANOGRAPHIC INSTITUTE	MS # 14 CHALLENGER HOUSE	WOODS HOLE	MA	02543	BARNSTABLE	USA	Environmental Health	001	17	7/4/2013	NON-COMPETING CONTINUATION	$30,381
2013	2013	WOODS HOLE OCEANOGRAPHIC INSTITUTE	MS # 14 CHALLENGER HOUSE	WOODS HOLE	MA	02543	BARNSTABLE	USA	Environmental Health	000	17	11/29/2012	NON-COMPETING CONTINUATION	$341,790
														Subtotal = $372,171

Issue Date FY: 2012 ( Subtotal = $373,732 )
2012	2012	WOODS HOLE OCEANOGRAPHIC INSTITUTE	MS # 14 CHALLENGER HOUSE	WOODS HOLE	MA	02543	BARNSTABLE	USA	Environmental Health	000	16	12/1/2011	NON-COMPETING CONTINUATION	$336,359
2012	2012	WOODS HOLE OCEANOGRAPHIC INSTITUTE	MS # 14 CHALLENGER HOUSE	WOODS HOLE	MA	02543	BARNSTABLE	USA	Environmental Health	001	16	3/14/2012	NON-COMPETING CONTINUATION	$37,373
														Subtotal = $373,732

Issue Date FY: 2011 ( Subtotal = $381,223 )
2011	2011	WOODS HOLE OCEANOGRAPHIC INSTITUTE	MS # 14 CHALLENGER HOUSE	WOODS HOLE	MA	02543	BARNSTABLE	USA	Environmental Health	001	15	6/3/2011	NON-COMPETING CONTINUATION	$34,657
2011	2011	WOODS HOLE OCEANOGRAPHIC INSTITUTE	MS # 14 CHALLENGER HOUSE	WOODS HOLE	MA	02543	BARNSTABLE	USA	Environmental Health	000	15	12/1/2010	NON-COMPETING CONTINUATION	$346,566
														Subtotal = $381,223

Issue Date FY: 2010 ( Subtotal = $378,916 )
2010	2010	WOODS HOLE OCEANOGRAPHIC INSTITUTE	MS # 14 CHALLENGER HOUSE	WOODS HOLE	MA	02543	BARNSTABLE	USA	Environmental Health	000	14	1/15/2010	COMPETING CONTINUATION	$378,916
														Subtotal = $378,916

Issue Date FY: 2007 ( Subtotal = $340,738 )
2007	2007	WOODS HOLE OCEANOGRAPHIC INSTITUTE	MS # 14 CHALLENGER HOUSE	WOODS HOLE	MA	02543	BARNSTABLE	USA	Environmental Health	000	13	4/9/2007	NON-COMPETING CONTINUATION	$340,738
														Subtotal = $340,738

Issue Date FY: 2006 ( Subtotal = $345,268 )
2006	2006	WOODS HOLE OCEANOGRAPHIC INSTITUTE	MS # 14 CHALLENGER HOUSE	WOODS HOLE	MA	02543	BARNSTABLE	USA	Environmental Health	000	12	4/20/2006	NON-COMPETING CONTINUATION	$345,268
														Subtotal = $345,268

Issue Date FY: 2005 ( Subtotal = $346,301 )
2005	2005	WOODS HOLE OCEANOGRAPHIC INSTITUTE	MS # 14 CHALLENGER HOUSE	WOODS HOLE	MA	02543	BARNSTABLE	USA	Environmental Health	000	11	4/25/2005	NON-COMPETING CONTINUATION	$346,301
														Subtotal = $346,301

Issue Date FY: 2004 ( Subtotal = $339,371 )
2004	2004	WOODS HOLE OCEANOGRAPHIC INSTITUTE	MS # 14 CHALLENGER HOUSE	WOODS HOLE	MA	02543	BARNSTABLE	USA	Environmental Health	000	10	4/30/2004	NON-COMPETING CONTINUATION	$339,371
														Subtotal = $339,371

Issue Date FY: 2003 ( Subtotal = $357,784 )
2003	2003	WOODS HOLE OCEANOGRAPHIC INSTITUTE	MS # 14 CHALLENGER HOUSE	WOODS HOLE	MA	02543	BARNSTABLE	USA	Environmental Health	000	9	6/16/2003	COMPETING CONTINUATION	$357,784
														Subtotal = $357,784

Issue Date FY: 2001 ( Subtotal = $212,005 )
2001	2001	WOODS HOLE OCEANOGRAPHIC INSTITUTE	MS # 14 CHALLENGER HOUSE	WOODS HOLE	MA	02543	BARNSTABLE	USA	Environmental Health	000	8	8/27/2001	NON-COMPETING CONTINUATION	$212,005
														Subtotal = $212,005

Issue Date FY: 2000 ( Subtotal = $237,506 )
2000	2000	WOODS HOLE OCEANOGRAPHIC INSTITUTE	MS # 14 CHALLENGER HOUSE	WOODS HOLE	MA	02543	BARNSTABLE	USA	Environmental Health	000	7	8/30/2000	NON-COMPETING CONTINUATION	$237,506
														Subtotal = $237,506

Issue Date FY: 1999 ( Subtotal = $194,135 )
1999	1999	WOODS HOLE OCEANOGRAPHIC INSTITUTE	MS # 14 CHALLENGER HOUSE	WOODS HOLE	MA	02543	BARNSTABLE	USA	Environmental Health	000	6	7/26/1999	COMPETING CONTINUATION	$194,135
														Subtotal = $194,135

Grand Total All Awards = $4,261,325

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AHR Signaling in Mammalian and Non-Mammalian Models

Award Number: R01ES006272

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/10/1992

PERIOD OF PERFORMANCE END DATE: 08/30/2016

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