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Metabolic and xenobiotic control of thyroid hormone metabolism

Award Number: R01DK077148
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/15/2025
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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Metabolic and xenobiotic control of thyroid hormone metabolism - ABSTRACT Thyroid hormones (TH) play a critical role in development. In the embryo, plasma T3 is relatively low but TH signaling can be enhanced by expression of Dio2, the deiodinase that mediates local T3 production. The timing of the D2-T3 activation varies among tissues, e.g. embryonic day 17 (E17) in brown adipose tissue (BAT), or post-natal day 15 in the cochlea (P15). During the last funding period we discovered a D2-T3 peak in the developing liver (P1-P2), coincidental with the C/EBPa-induced maturation of hepatoblasts to hepatocytes; Dio2 expression in liver is silenced thereafter. By creating a liver-specific Dio2KO mouse (Alb-D2KO) we made the fascinating discovery that inactivation of the D2-T3 peak modifies the liver transcriptome of the adult mouse, with reduced expression of genes involved in lipid metabolism. The adult Alb-D2KO mouse exhibits a dramatic phenotype of reduced susceptibility to obesity, liver steatosis and hyperlipidemia. How could a brief perinatal peak of D2-T3 activate TH receptors (TR) and produce these changes? Hepatocytes undergo massive postnatal epigenetic reprogramming, including changes in the DNA methylation status, some of which we now know depend on D2-T3. We identified 1,508 CpG sites of DNA hypermethylation (H-sites) in the adult Alb- D2KO liver genome. Thus, the perinatal D2-T3 peak ultimately affects the chromatin packing status and transcriptional activity of adult hepatocytes, reducing the expression of 1,525 genes (RNA-seq). The proposed studies are to identify the epigenetic mechanisms initiated by the perinatal D2-T3 peak in the liver. This is absolutely novel and exciting as we will learn how deiodinase-mediated TH signaling affects liver development, shaping gene expression in the adult organ.


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: 2025 ( Subtotal = $438,571 )
2025	2025	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	12	4/24/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$438,571
2025	2025	UNIVERSITY OF TEXAS MEDICAL BRANCH AT GALVESTON	301 UNIVERSITY BLVD	GALVESTON	TX	77555	GALVESTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	12	6/17/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$149,894
2025	2024	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	11	6/17/2025	NON-COMPETING CONTINUATION	-$149,894
2025	2024	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	11	4/23/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $438,571

Issue Date FY: 2024 ( Subtotal = $428,667 )
2024	2024	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	11	5/9/2024	NON-COMPETING CONTINUATION	$428,667
														Subtotal = $428,667

Issue Date FY: 2023 ( Subtotal = $462,528 )
2023	2023	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	3/16/2023	COMPETING CONTINUATION	$462,528
														Subtotal = $462,528

Issue Date FY: 2018 ( Subtotal = $0 )
2018	2016	RUSH UNIVERSITY MEDICAL CENTER	1653 W CONGRESS PRKWY	CHICAGO	IL	60612	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	12/7/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $332,775 )
2016	2016	RUSH-PRESBYTERIAN-ST LUKE`S MEDICAL CENTER	1700 WEST VAN BUREN STREET	CHICAGO	IL	60612	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	8/22/2016	NON-COMPETING CONTINUATION	$332,775
														Subtotal = $332,775

Issue Date FY: 2015 ( Subtotal = $332,775 )
2015	2015	RUSH-PRESBYTERIAN-ST LUKE`S MEDICAL CENTER	1700 WEST VAN BUREN STREET	CHICAGO	IL	60612	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	6/15/2015	NON-COMPETING CONTINUATION	$332,775
														Subtotal = $332,775

Issue Date FY: 2014 ( Subtotal = $332,775 )
2014	2014	RUSH-PRESBYTERIAN-ST LUKE`S MEDICAL CENTER	1700 WEST VAN BUREN STREET	CHICAGO	IL	60612	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	7	7/8/2014	NON-COMPETING CONTINUATION	$332,775
2014	2013	UNIVERSITY OF MIAMI	P.O. BOX 248106	CORAL GABLES	FL	33124	MIAMI-DADE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	7/2/2014	COMPETING CONTINUATION	-$150,127
2014	2013	RUSH-PRESBYTERIAN-ST LUKE`S MEDICAL CENTER	1700 WEST VAN BUREN STREET	CHICAGO	IL	60612	COOK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	7/2/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$150,127
														Subtotal = $332,775

Issue Date FY: 2013 ( Subtotal = $333,863 )
2013	2013	UNIVERSITY OF MIAMI	P.O. BOX 248106	CORAL GABLES	FL	33124	MIAMI-DADE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	8/2/2013	COMPETING CONTINUATION	$1,088
2013	2013	UNIVERSITY OF MIAMI	P.O. BOX 248106	CORAL GABLES	FL	33124	MIAMI-DADE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	7/12/2013	COMPETING CONTINUATION	$332,775
														Subtotal = $333,863

Issue Date FY: 2012 ( Subtotal = $0 )
2012	2010	UNIVERSITY OF MIAMI	POST OFFICE BOX 248106	CORAL GABLES	FL	33124	MIAMI-DADE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	1/5/2012	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2010 ( Subtotal = $374,103 )
2010	2010	UNIVERSITY OF MIAMI	P.O. BOX 248106	CORAL GABLES	FL	33124	MIAMI-DADE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	2/12/2010	NON-COMPETING CONTINUATION	$374,103
														Subtotal = $374,103

Issue Date FY: 2009 ( Subtotal = $377,882 )
2009	2009	UNIVERSITY OF MIAMI	P.O. BOX 248106	CORAL GABLES	FL	33124	MIAMI-DADE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	1/8/2009	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$263,145
2009	2009	UNIVERSITY OF MIAMI	P.O. BOX 248106	CORAL GABLES	FL	33124	MIAMI-DADE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	3	6/12/2009	SUPPLEMENT FOR EXPANSION	$85,499
2009	2009	UNIVERSITY OF MIAMI	P.O. BOX 248106	CORAL GABLES	FL	33124	MIAMI-DADE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	3	3/9/2009	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$29,238
2009	2008	BRIGHAM & WOMEN`S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	1/7/2009	NON-COMPETING CONTINUATION	$0
														Subtotal = $377,882

Issue Date FY: 2008 ( Subtotal = $322,849 )
2008	2008	BRIGHAM & WOMEN'S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	12/20/2007	NON-COMPETING CONTINUATION	$322,849
														Subtotal = $322,849

Issue Date FY: 2007 ( Subtotal = $329,438 )
2007	2007	BRIGHAM & WOMEN'S HOSPITAL	10 VINING STREET	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	12/26/2006	NEW	$329,438
														Subtotal = $329,438

Grand Total All Awards = $4,066,226

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Metabolic and xenobiotic control of thyroid hormone metabolism

Award Number: R01DK077148

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/15/2025

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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