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Defining OGT's Essential Functions to Guide Therapeutic Approaches

Award Number: R01GM094263
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2012
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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Defining OGT's Essential Functions to Guide Therapeutic Approaches - PROJECT SUMMARY O-GlcNAc transferase (OGT), an essential human protein, attaches N-acetylglucosamine (GlcNAc) to Ser/Thr residues of proteins in the nucleus and cytoplasm. Dysregulated OGT expression and activity have been linked to insulin resistance, diabetic complications, and cancer, making OGT a possible drug target. Developing approaches to exploit OGT as a target requires understanding its physiological roles and the mechanisms by which it achieves them. Studies to probe OGT's physiological roles have relied heavily on knockdown (KD) or conditional knockout (KO) experiments and the resulting phenotypes have been attributed to loss of O-GlcNAc. However, OGT has a second catalytic activity and also binds cellular proteins that it does not glycosylate; some phenotypes attributed to O-GlcNAc loss may therefore be due to loss of other activities. Previously, the importance of OGT's catalytic and noncatalytic functions could not be assessed because methods to replace endogenous OGT with variants did not exist. We have now established methods to replace OGT and will analyze cells containing specifically altered copies to deconvolute OGT's physiological roles. Growth phenotypes, quantitative proteomics, and biochemistry will be used to address several questions. Is OGT's noncatalytic scaffolding activity a major driver of physiology and what pathways are linked to it? What is the shortest OGT construct that still supports cell survival and what proteins does it glycosylate and bind? How do OGT's substrates and binding partners interact with the TPR domain and are there opportunities to target specific regions of this domain? We will also use a small molecule inhibitor we recently developed in a chemogenomics screen to identify genetic vulnerabilities to loss of O-GlcNAc. In addition to advancing scientific knowledge about one of the most fundamentally important proteins in mammalian biology, the work in this proposal will provide the foundation to guide approaches to exploit OGT as a therapeutic target.


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 = -$2,233 )
2025	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	12	4/16/2025	NON-COMPETING CONTINUATION	-$2,233
														Subtotal = -$2,233

Issue Date FY: 2024 ( Subtotal = $440,363 )
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	001	12	6/5/2024	NON-COMPETING CONTINUATION	$44,034
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	12	11/13/2023	NON-COMPETING CONTINUATION	$396,329
														Subtotal = $440,363

Issue Date FY: 2023 ( Subtotal = $518,080 )
2023	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	002	11	2/14/2023	NON-COMPETING CONTINUATION	$44,034
2023	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	11	11/11/2022	NON-COMPETING CONTINUATION	$396,329
2023	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	001	11	11/16/2022	SUPPLEMENT FOR EXPANSION	$77,717
														Subtotal = $518,080

Issue Date FY: 2022 ( Subtotal = $520,712 )
2022	2022	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	001	10	12/7/2021	SUPPLEMENT FOR EXPANSION	$77,584
2022	2022	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	002	10	5/17/2022	NON-COMPETING CONTINUATION	$44,312
2022	2022	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	10	11/10/2021	NON-COMPETING CONTINUATION	$398,816
														Subtotal = $520,712

Issue Date FY: 2021 ( Subtotal = $515,542 )
2021	2021	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	9	12/9/2020	COMPETING CONTINUATION	$445,542
2021	2021	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	001	9	7/16/2021	SUPPLEMENT FOR EXPANSION	$70,000
														Subtotal = $515,542

Issue Date FY: 2020 ( Subtotal = -$1 )
2020	2019	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	8	8/21/2020	NON-COMPETING CONTINUATION	-$1
														Subtotal = -$1

Issue Date FY: 2019 ( Subtotal = $433,587 )
2019	2019	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	8	2/26/2019	NON-COMPETING CONTINUATION	$433,587
														Subtotal = $433,587

Issue Date FY: 2018 ( Subtotal = $433,633 )
2018	2018	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	001	7	5/15/2018	NON-COMPETING CONTINUATION	$43,364
2018	2018	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	7	2/5/2018	NON-COMPETING CONTINUATION	$390,269
														Subtotal = $433,633

Issue Date FY: 2017 ( Subtotal = $429,423 )
2017	2017	HARVARD COLLEGE, PRESIDENT & FELLOWS OF	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	6	2/7/2017	NON-COMPETING CONTINUATION	$386,479
2017	2017	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	001	6	6/8/2017	NON-COMPETING CONTINUATION	$42,944
														Subtotal = $429,423

Issue Date FY: 2016 ( Subtotal = $429,423 )
2016	2016	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	002	5	3/23/2016	COMPETING CONTINUATION	$429,423
2016	2015	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	4	3/18/2016	SUPPLEMENT FOR EXPANSION	$0
2016	2015	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	001	4	3/18/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $429,423

Issue Date FY: 2015 ( Subtotal = $544,992 )
2015	2015	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	001	4	7/13/2015	SUPPLEMENT FOR EXPANSION	$27,523
2015	2015	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	4	1/26/2015	NON-COMPETING CONTINUATION	$517,469
														Subtotal = $544,992

Issue Date FY: 2014 ( Subtotal = $517,469 )
2014	2014	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	3	1/30/2014	NON-COMPETING CONTINUATION	$465,721
2014	2014	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	001	3	3/24/2014	NON-COMPETING CONTINUATION	$51,748
														Subtotal = $517,469

Issue Date FY: 2013 ( Subtotal = $498,749 )
2013	2013	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	001	2	6/13/2013	NON-COMPETING CONTINUATION	$33,595
2013	2013	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	2	1/18/2013	NON-COMPETING CONTINUATION	$465,154
														Subtotal = $498,749

Issue Date FY: 2012 ( Subtotal = $530,282 )
2012	2012	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Biomedical Research and Research Training	000	1	1/30/2012	NEW	$530,282
														Subtotal = $530,282

Grand Total All Awards = $5,810,021

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Defining OGT's Essential Functions to Guide Therapeutic Approaches

Award Number: R01GM094263

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2012

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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