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Thyroid Hormone Receptor Mislocalization and Pathogenesis

Award Number: R15DK058028
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: 07/01/2001
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Thyroid Hormone Receptor Mislocalization and Pathogenesis - PROJECT SUMMARY Thyroid hormone receptors (TRs) are essential transcription factors that either activate or repress the expression of target genes in response to thyroid hormone (T3). The proposed research explores a novel facet of our overarching hypothesis that mislocalization of TR contributes to pathogenesis, by investigating the molecular mechanism by which acetylation acts as a regulatory switch for TR localization. Our prior studies supported by 2 R15 DK058028 provide a robust premise for the proposed research. Although TRs primarily reside in the nucleus, we have shown that they shuttle rapidly between the nucleus and cytoplasm. We have identified multiple nuclear localization signals and nuclear export signals within TR that interact with importins and exportins, respectively, to mediate translocation into the nucleus. Our published data show that acetylation mimetics of TR promote cytoplasmic localization of TR but at the same time enhance ligand-dependent transcriptional activity. In contrast, mutants that mimic nonacetylated TR have reduced intranuclear mobility, greater nuclear retention, and impaired ligand-dependent transcriptional activity. Based on these published data and other preliminary findings, our working model implicates acetylation as a key molecular switch for modulating TR localization, intranuclear mobility, and transcriptional activity. Here, we will address the following unanswered questions: Is there one key acetylation site that alters nucleocytoplasmic distribution, intranuclear mobility, and transcriptional activity? Is TR modification compartment-specific? Which acetyltransferase(s) and deacetylase(s) regulate TR modification? Does TR acetylation affect its protein- protein interactions, stability, or ubiquitin-mediated degradation? We will use a multi-pronged approach of transient transfection of mammalian cells followed by quantitative fluorescence microscopy, fluorescence recovery after photobleaching (FRAP), luciferase reporter assays, pharmacological inhibitor screening, and coimmunoprecipitation assays, to test our model. In addition, acetylation sites will be confirmed by MS/MS analysis, and a novel TR-based NanoBRET assay will be developed to study protein-protein interactions. Finally, we will investigate whether mutations in TR linked to Resistance to Thyroid Hormone (RTH) syndrome respond aberrantly to the acetylation switch, providing insight into the correlation between altered trafficking signals in TR and endocrine disorders. Elucidating how TR acetylation is modulated will enhance understanding of the impact this pivotal post-translational modification has upon T3 signaling. A team of talented undergraduates will be actively engaged in the proposed research, gaining hands-on experience with the scientific process, from project design and execution to publication and/or presentation.


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 = $0 )
2025	2022	COLLEGE OF WILLIAM AND MARY	1314 S MOUNT VERNON AVE	WILLIAMSBURG	VA	23185	JAMES CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	2/17/2025	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	COLLEGE OF WILLIAM & MARY, THE	261 RICHMOND RD	WILLIAMSBURG	VA	23185	JAMES CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	11/2/2022	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $425,824 )
2022	2022	COLLEGE OF WILLIAM & MARY, THE	261 RICHMOND RD	WILLIAMSBURG	VA	23185	JAMES CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	2/10/2022	COMPETING CONTINUATION	$425,824
2022	2018	COLLEGE OF WILLIAM & MARY, THE	261 RICHMOND RD	WILLIAMSBURG	VA	23185	JAMES CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	3/24/2022	COMPETING CONTINUATION	$0
														Subtotal = $425,824

Issue Date FY: 2021 ( Subtotal = -$1 )
2021	2015	COLLEGE OF WILLIAM & MARY, THE	261 RICHMOND RD	WILLIAMSBURG	VA	23185	JAMES CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	4	10/3/2020	COMPETING CONTINUATION	$1
2021	2015	COLLEGE OF WILLIAM & MARY, THE	261 RICHMOND RD	WILLIAMSBURG	VA	23185	JAMES CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	10/3/2020	COMPETING CONTINUATION	-$1
2021	2015	COLLEGE OF WILLIAM & MARY, THE	261 RICHMOND RD	WILLIAMSBURG	VA	23185	JAMES CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	10/1/2020	COMPETING CONTINUATION	-$1
														Subtotal = -$1

Issue Date FY: 2018 ( Subtotal = $405,273 )
2018	2018	COLLEGE OF WILLIAM & MARY, THE	261 RICHMOND RD	WILLIAMSBURG	VA	23185	JAMES CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	9/5/2018	COMPETING CONTINUATION	$405,273
														Subtotal = $405,273

Issue Date FY: 2015 ( Subtotal = $421,729 )
2015	2015	COLLEGE OF WILLIAM & MARY	P.O. BOX 8795	WILLIAMSBURG	VA	23187	WILLIAMSBURG CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	9/15/2015	COMPETING CONTINUATION	$421,729
														Subtotal = $421,729

Issue Date FY: 2010 ( Subtotal = $47,393 )
2010	2010	COLLEGE OF WILLIAM & MARY	POST OFFICE BOX 8795	WILLIAMSBURG	VA	23187	WILLIAMSBURG CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	3	9/30/2010	SUPPLEMENT FOR EXPANSION	$0
2010	2010	COLLEGE OF WILLIAM & MARY	P.O. BOX 8795	WILLIAMSBURG	VA	23187	WILLIAMSBURG CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	9/20/2010	SUPPLEMENT FOR EXPANSION	$47,393
2010	2009	COLLEGE OF WILLIAM & MARY	POST OFFICE BOX 8795	WILLIAMSBURG	VA	23187	WILLIAMSBURG CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	9/30/2010	COMPETING CONTINUATION	$0
														Subtotal = $47,393

Issue Date FY: 2009 ( Subtotal = $204,105 )
2009	2009	COLLEGE OF WILLIAM & MARY	P.O. BOX 8795	WILLIAMSBURG	VA	23187	WILLIAMSBURG CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	6/3/2009	COMPETING CONTINUATION	$204,105
														Subtotal = $204,105

Issue Date FY: 2005 ( Subtotal = $207,920 )
2005	2005	COLLEGE OF WILLIAM & MARY	POST OFFICE BOX 8795	WILLIAMSBURG	VA	23187	WILLIAMSBURG CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	7/14/2005	COMPETING CONTINUATION	$207,920
														Subtotal = $207,920

Issue Date FY: 2001 ( Subtotal = $145,000 )
2001	2001	COLLEGE OF WILLIAM & MARY	POST OFFICE BOX 8795	WILLIAMSBURG	VA	23187	WILLIAMSBURG CITY	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	6/25/2001	NEW	$145,000
														Subtotal = $145,000

Grand Total All Awards = $1,857,243

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Thyroid Hormone Receptor Mislocalization and Pathogenesis

Award Number: R15DK058028

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: 07/01/2001

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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