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Corepressor regulation of nuclear receptor action

Award Number: R01DK056123
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Corepressor regulation of nuclear receptor action - Thyroid hormone (TH) regulates numerous key physiologic processes that are essential for normal development and then physiologic action in adulthood. Furthermore, specific targeting of TH signaling may improve metabolic disease, including hypercholesterolemia and non-alcoholic steatohepatitis. While circulating thyroid hormone levels are used in humans to interpret thyroid status they are just the tip of the iceberg as cellular TH availability is regulated by transporters, deiodinases, and coregulators of the thyroid hormone receptor isoforms (TRs). Thus, cellular action of TH can be disassociated from circulating TH levels in a particular tissue. We have previously shown that the nuclear corepressors, NCoR1 and SMRT are critical regulators of cellular TH action by regulating both the sensitivity of the TR for available ligand and the ability of the TR to silence or repress in gene expression in hypothyroidism. However, the full mechanism by which NCoR1/SMRT or other potential corepressors function remains to be determined. To gain further insight into nuclear corepressor action we propose three specific aims. In the first Aim we will determine how NCoR1 and SMRT mediate specificity in their interactions with nuclear receptors in context of their recruitment to the genome. In the second Aim we will identify novel pathways that the TRs employ, independent of NCoR1/SMRT to mediate repression in hypothyroidism or in the syndromes of resistance to thyroid hormone. Finally, in the third Aim we will explore why loss of NCoR1 and SMRT in adult life leads to immediate lethality. We hypothesize that NCoR1/SMRT have redundant roles in regulating nutrient availability. Together completion of these Aims will provide key insight into how NCOR1 and SMRT and potentially other corepressors function to regulate thyroid hormone action and metabolic function and open up new avenues to target these pathways in the treatment of metabolic disease.


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 = -$40,283 )
2025	2023	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	22	4/22/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$40,283
														Subtotal = -$40,283

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	22	12/11/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$281,917
2024	2022	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	21	12/11/2023	NON-COMPETING CONTINUATION	-$281,917
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $669,900 )
2023	2023	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	22	4/18/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$669,900
2023	2022	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	21	4/17/2023	NON-COMPETING CONTINUATION	$0
2023	2022	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	21	4/17/2023	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $669,900

Issue Date FY: 2022 ( Subtotal = $555,960 )
2022	2022	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	21	4/28/2022	SUPPLEMENT FOR EXPANSION	$0
2022	2022	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	21	12/29/2021	NON-COMPETING CONTINUATION	$381,375
2022	2022	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	21	5/9/2022	NON-COMPETING CONTINUATION	$42,375
2022	2022	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	21	4/25/2022	SUPPLEMENT FOR EXPANSION	$132,210
														Subtotal = $555,960

Issue Date FY: 2021 ( Subtotal = $423,750 )
2021	2021	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	20	12/30/2020	NON-COMPETING CONTINUATION	$381,375
2021	2021	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	20	2/8/2021	NON-COMPETING CONTINUATION	$42,375
2021	2020	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	19	6/5/2021	COMPETING CONTINUATION	$3,393
2021	2018	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	1300 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	18	6/5/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$3,393
														Subtotal = $423,750

Issue Date FY: 2020 ( Subtotal = $423,750 )
2020	2020	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	407 E 61ST ST RM 106 1ST FL	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	19	2/26/2020	COMPETING CONTINUATION	$423,750
2020	2018	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	407 E 61ST ST RM 106 1ST FL	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	18	2/20/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $423,750

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2018	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	407 E 61ST ST RM 106 1ST FL	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	18	11/9/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$167,366
2019	2018	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	407 E 61ST ST RM 106 1ST FL	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	18	10/31/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2019	2017	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	16	11/9/2018	NON-COMPETING CONTINUATION	-$167,366
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $392,556 )
2018	2018	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	407 E 61ST ST RM 106 1ST FL	NEW YORK	NY	10065	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	18	8/13/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$392,556
2018	2018	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	17	5/10/2018	NON-COMPETING CONTINUATION	$386,898
2018	2018	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	17	8/13/2018	NON-COMPETING CONTINUATION	-$386,898
														Subtotal = $392,556

Issue Date FY: 2017 ( Subtotal = $386,898 )
2017	2017	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	16	5/1/2017	NON-COMPETING CONTINUATION	$348,207
2017	2017	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	16	6/15/2017	NON-COMPETING CONTINUATION	$38,691
														Subtotal = $386,898

Issue Date FY: 2016 ( Subtotal = $386,898 )
2016	2016	BETH ISRAEL HOSPITAL	330 BROOKLINE AVENUE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	15	4/15/2016	NON-COMPETING CONTINUATION	$386,898
														Subtotal = $386,898

Issue Date FY: 2015 ( Subtotal = $405,398 )
2015	2015	BETH ISRAEL HOSPITAL	330 BROOKLINE AVENUE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	14	6/10/2015	COMPETING CONTINUATION	$405,398
2015	2013	BETH ISRAEL HOSPITAL	330 BROOKLINE AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	13	6/5/2015	NON-COMPETING CONTINUATION	$0
														Subtotal = $405,398

Issue Date FY: 2013 ( Subtotal = $348,254 )
2013	2013	BETH ISRAEL HOSPITAL	330 BROOKLINE AVENUE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	13	7/26/2013	NON-COMPETING CONTINUATION	$348,254
														Subtotal = $348,254

Issue Date FY: 2012 ( Subtotal = $360,885 )
2012	2012	BETH ISRAEL HOSPITAL	330 BROOKLINE AVENUE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	12	7/31/2012	NON-COMPETING CONTINUATION	$360,885
														Subtotal = $360,885

Issue Date FY: 2011 ( Subtotal = $360,885 )
2011	2011	BETH ISRAEL HOSPITAL	330 BROOKLINE AVENUE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	11	7/27/2011	NON-COMPETING CONTINUATION	$360,885
														Subtotal = $360,885

Issue Date FY: 2010 ( Subtotal = $434,791 )
2010	2010	BETH ISRAEL HOSPITAL	330 BROOKLINE AVENUE	BOSTON	MA	02215	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	8/13/2010	COMPETING CONTINUATION	$434,791
														Subtotal = $434,791

Issue Date FY: 2008 ( Subtotal = $276,442 )
2008	2008	BETH ISRAEL HOSPITAL	330 BROOKLINE AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	7/8/2008	NON-COMPETING CONTINUATION	$276,442
														Subtotal = $276,442

Issue Date FY: 2007 ( Subtotal = $282,084 )
2007	2007	BETH ISRAEL HOSPITAL	330 BROOKLINE AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	6/14/2007	NON-COMPETING CONTINUATION	$282,084
														Subtotal = $282,084

Grand Total All Awards = $7,561,178

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Corepressor regulation of nuclear receptor action

Award Number: R01DK056123

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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