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E2A/HEB MEDIATED TRANSCRIPTIONAL REGULATION IN T CELL DEVELOPMENT

Award Number: R01GM059638
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: 08/01/1999
PERIOD OF PERFORMANCE END DATE: 12/31/2022

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E2A/HEB MEDIATED TRANSCRIPTIONAL REGULATION IN T CELL DEVELOPMENT - E2A/HEB MEDIATED TRANSCRIPTIONAL REGULATION IN T CELL DEVELOPMENT Abstract T lymphocyte development in the thymus gives rise to multiple lineages of T cells that are clearly separated from each other based on their distinct effector fates and associated immune functions. Invariant natural killer T (iNKT) cells represent a group of innate-like T cells produced in parallel with CD4 helper and CD8 killer lineage T cells that provide adaptive immunity. In contrast to adaptive T cells, which constitute the vast clonal diversity but remain mostly functionally naïve in circulation, iNKT cells have already acquired effector functions upon maturation in the thymus or arrival at the peripheral tissues. This unique feature endorses iNKT cells to play important roles in the early phase of immune defense, long before the elapsing window needed for clonal activation and expansion of antigen specific CD4 helper or CD8 killer T cells. Because iNKT cells use a semi- invariant T cell receptor (TCR) that can be stimulated with small lipid antigens to provide potent effector function, they have a great potential to be applied to cell-based immune therapy. However, due to lack of understanding of the regulatory mechanisms underpinning iNKT lineage development and homeostatic maintenance of the effector populations, therapeutic manipulation of iNKT cells in vivo or adoptive transfer of ex vivo expanded iNKT cells still remain in early phase of clinical trials. Our recent studies have revealed a critical role for E-protein transcription factors, encoded by the E2A and HEB genes, in driving iNKT lineage specification and expansion. Strikingly, we saw a dramatic enhancement of iNKT cell development and expansion upon deletion of the Id2 and Id3 genes, which encode inhibitors of E-proteins. The expansion of iNKT cells, induced by Id gene deletion, eventually drives their malignant transformation into iNKT lymphomas in young adult mice. These findings offer a new angle of approach to uncovering the developmental timing and regulatory pathways of iNKT lineage development and expansion. In this proposal we will leverage the mouse genetic tools established in our lab to define the separate roles of E proteins in iNKT lineage commitment and subsequent clonal expansion. iNKT cells are highly conserved between mice and humans in regards to their developmental origin, antigenic specificity, and functionality. The outcome of the proposed research will provide new strategies for controlled manipulation of iNKT cells that can be used in immune therapy, either alone or in combination with the adaptive T cells, without the risk of malignant transformation.


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: 2024 ( Subtotal = -$23,841 )
2024	2021	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Biomedical Research and Research Training	000	20	10/17/2023	NON-COMPETING CONTINUATION	-$23,841
														Subtotal = -$23,841

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	000	20	11/19/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $455,072 )
2021	2021	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	000	20	6/9/2021	NON-COMPETING CONTINUATION	$455,072
														Subtotal = $455,072

Issue Date FY: 2020 ( Subtotal = $455,072 )
2020	2020	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	000	19	6/16/2020	NON-COMPETING CONTINUATION	$455,072
														Subtotal = $455,072

Issue Date FY: 2019 ( Subtotal = $455,072 )
2019	2019	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	000	18	6/17/2019	NON-COMPETING CONTINUATION	$455,072
														Subtotal = $455,072

Issue Date FY: 2018 ( Subtotal = $452,251 )
2018	2018	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	000	17	7/17/2018	COMPETING CONTINUATION	$452,251
2018	2016	DUKE UNIVERSITY	2200 W MAIN ST STE 710	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	001	16	7/17/2018	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $452,251

Issue Date FY: 2016 ( Subtotal = $426,667 )
2016	2016	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	000	16	2/11/2016	EXTENSION WITH OR WITHOUT FUNDS	$426,667
														Subtotal = $426,667

Issue Date FY: 2015 ( Subtotal = $426,667 )
2015	2015	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	000	15	3/18/2015	NON-COMPETING CONTINUATION	$426,667
														Subtotal = $426,667

Issue Date FY: 2014 ( Subtotal = $426,667 )
2014	2014	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	000	14	3/7/2014	NON-COMPETING CONTINUATION	$426,667
														Subtotal = $426,667

Issue Date FY: 2013 ( Subtotal = $426,667 )
2013	2013	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	000	13	3/7/2013	COMPETING CONTINUATION	$426,667
														Subtotal = $426,667

Issue Date FY: 2011 ( Subtotal = $321,081 )
2011	2011	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	000	12	8/1/2011	NON-COMPETING CONTINUATION	$321,081
														Subtotal = $321,081

Issue Date FY: 2010 ( Subtotal = $324,324 )
2010	2010	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	000	11	7/15/2010	NON-COMPETING CONTINUATION	$324,324
														Subtotal = $324,324

Issue Date FY: 2009 ( Subtotal = $327,600 )
2009	2009	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	000	10	8/7/2009	NON-COMPETING CONTINUATION	$327,600
														Subtotal = $327,600

Issue Date FY: 2008 ( Subtotal = $327,600 )
2008	2008	DUKE UNIVERSITY	BOX 104004	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	000	9	9/22/2008	COMPETING CONTINUATION	$327,600
														Subtotal = $327,600

Issue Date FY: 2007 ( Subtotal = $299,342 )
2007	2007	DUKE UNIVERSITY	BOX 104135	DURHAM	NC	27708	DURHAM	USA	Biomedical Research and Research Training	000	8	12/1/2006	NON-COMPETING CONTINUATION	$299,342
														Subtotal = $299,342

Issue Date FY: 2006 ( Subtotal = $308,282 )
2006	2006	DUKE UNIVERSITY	POST OFFICE BOX 40005	DURHAM	NC	27706	DURHAM	USA	Biomedical Research and Research Training	000	7	12/8/2005	NON-COMPETING CONTINUATION	$308,282
														Subtotal = $308,282

Issue Date FY: 2005 ( Subtotal = $315,700 )
2005	2005	DUKE UNIVERSITY	POST OFFICE BOX 40005	DURHAM	NC	27706	DURHAM	USA	Biomedical Research and Research Training	000	6	12/20/2004	NON-COMPETING CONTINUATION	$315,700
														Subtotal = $315,700

Issue Date FY: 2004 ( Subtotal = $315,700 )
2004	2004	DUKE UNIVERSITY	POST OFFICE BOX 40005	DURHAM	NC	27706	DURHAM	USA	Biomedical Research and Research Training	000	5	11/27/2003	COMPETING CONTINUATION	$315,700
														Subtotal = $315,700

Issue Date FY: 2002 ( Subtotal = $261,514 )
2002	2002	DUKE UNIVERSITY	POST OFFICE BOX 40005	DURHAM	NC	27706	DURHAM	USA	Biomedical Research and Research Training	000	4	7/29/2002	NON-COMPETING CONTINUATION	$261,514
														Subtotal = $261,514

Issue Date FY: 2001 ( Subtotal = $326,553 )
2001	2001	DUKE UNIVERSITY	POST OFFICE BOX 40005	DURHAM	NC	27706	DURHAM	USA	Biomedical Research and Research Training	001	2	2/12/2001	SUPPLEMENT FOR EXPANSION	$69,485
2001	2001	DUKE UNIVERSITY	POST OFFICE BOX 40005	DURHAM	NC	27706	DURHAM	USA	Biomedical Research and Research Training	000	3	7/30/2001	NON-COMPETING CONTINUATION	$257,068
														Subtotal = $326,553

Issue Date FY: 2000 ( Subtotal = $249,759 )
2000	2000	Duke University	OFFICE OF SPONSORED PROGRAMS	DURHAM	NC	27705	DURHAM	USA	Biomedical Research and Research Training	000	2	7/24/2000	NON-COMPETING CONTINUATION	$249,759
														Subtotal = $249,759

Issue Date FY: 1999 ( Subtotal = $299,584 )
1999	1999	Duke University	OFFICE OF SPONSORED PROGRAMS	DURHAM	NC	27705	DURHAM	USA	Biomedical Research and Research Training	000	1	7/26/1999	NEW	$299,584
														Subtotal = $299,584

Grand Total All Awards = $7,177,333

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E2A/HEB MEDIATED TRANSCRIPTIONAL REGULATION IN T CELL DEVELOPMENT

Award Number: R01GM059638

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: 08/01/1999

PERIOD OF PERFORMANCE END DATE: 12/31/2022

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