Tuesday, August 19, 2025 8/19/2025

Structure, Function and Applications of Inteins

Award Number: R01GM086868
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: 09/01/1999
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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Structure, Function and Applications of Inteins - SUMMARY: Chemistry-driven strategies that allow proteins to be manipulated in ways not permitted by standard genetics are now indispensable tools in both basic and applied aspects of biomedical science. Of the various platform technologies in common use, those that rely on manipulation of intein-mediated protein splicing have proven especially powerful owing to broad compatibility with both in vitro and in vivo applications. Work performed during the current funding period has led to the discovery, characterization and eventual engineering of several inteins, especially those split into two mutually-dependent fragments that support protein trans-splicing upon complexation. We have employed these ‘protein ligases’ to solve a number of biochemical problems, primarily in the chromatin biology area. In the next phase of this program, we will exploit recent advances in our understanding of protein trans-splicing, to develop split intein tools designed to address a series of problems also in the area of epigenetics. Accordingly, a concerted protein ‘transposition’ reaction will be developed that allows replacement of internal regions of intact target proteins with synthetic cassettes containing chemical probes such as crosslinkers and photosensitizers (Aim 1). This cut-and paste system will be used to define and manipulate epigenetic complexes involved in higher-order chromatin structure. We will also develop various controllable versions of split inteins for use in both basic science and synthetic biology applications. In one line of enquiry (Aim 2), we will use these tools to rapidly generate oncofusion proteins such AML-ETO, thereby allowing characterization of the early stages of cell transformation. Lastly, in Aim 3, we will develop protein ‘actuators’ that use conditional protein splicing to convert a biochemical input of choice into a user-defined biochemical output. These ‘actuators’ will form the basis of epigenetic circuits that are dependent on Boolean logic operations and that allow higher- order chromatin complexes to be monitored in cells. While our focus is in the epigenetic area, we imagine that the technologies developed in the context of this work will expand the type of protein systems, and hence biological problems, accessible to interrogation through chemical biology strategies.


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 = $584,219 )
2025	2025	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	000	28	8/14/2025	NON-COMPETING CONTINUATION	$584,219
														Subtotal = $584,219

Issue Date FY: 2024 ( Subtotal = $584,219 )
2024	2024	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	000	27	8/28/2024	NON-COMPETING CONTINUATION	$584,219
														Subtotal = $584,219

Issue Date FY: 2023 ( Subtotal = $643,143 )
2023	2023	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	001	26	8/28/2023	NON-COMPETING CONTINUATION	$584,219
2023	2022	THE TRUSTEES OF PRINCETON UNIVERSITY	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	000	25	7/20/2023	COMPETING CONTINUATION	$58,924
														Subtotal = $643,143

Issue Date FY: 2022 ( Subtotal = $599,719 )
2022	2022	TRUSTEES OF PRINCETON UNIVERSITY, THE	1 NASSAU HALL	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	000	25	9/20/2022	COMPETING CONTINUATION	$599,719
														Subtotal = $599,719

Issue Date FY: 2011 ( Subtotal = $454,758 )
2011	2011	PRINCETON UNIVERSITY	POST OFFICE BOX 5292	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	002	14	9/5/2011	NON-COMPETING CONTINUATION	$470,104
2011	2010	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Biomedical Research and Research Training	000	12	8/24/2011	NON-COMPETING CONTINUATION	-$315,371
2011	2010	PRINCETON UNIVERSITY	POST OFFICE BOX 5292	PRINCETON	NJ	08544	MERCER	USA	Biomedical Research and Research Training	001	13	8/24/2011	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$300,025
														Subtotal = $454,758

Issue Date FY: 2010 ( Subtotal = $502,770 )
2010	2010	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Biomedical Research and Research Training	000	12	7/19/2010	NON-COMPETING CONTINUATION	$502,770
														Subtotal = $502,770

Issue Date FY: 2009 ( Subtotal = $558,725 )
2009	2009	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Biomedical Research and Research Training	003	11	7/21/2009	NON-COMPETING CONTINUATION	$496,074
2009	2009	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Trans-NIH Recovery Act Research Support	004	11	9/18/2009	SUPPLEMENT FOR EXPANSION	$62,651
2009	2008	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Biomedical Research and Research Training	000	10	7/21/2009	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2009	2008	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Biomedical Research and Research Training	001	10	8/12/2009	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$499,893
2009	2008	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Biomedical Research and Research Training	002	10	8/25/2009	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$499,893
														Subtotal = $558,725

Issue Date FY: 2008 ( Subtotal = $499,893 )
2008	2008	ROCKEFELLER UNIVERSITY	EAST 66TH STREET & YORK AVENUE	NEW YORK	NY	10021	NEW YORK	USA	Biomedical Research and Research Training	000	10	8/11/2008	OTHER REVISION	$499,893
														Subtotal = $499,893

Grand Total All Awards = $4,427,446

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Structure, Function and Applications of Inteins

Award Number: R01GM086868

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: 09/01/1999

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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