Tuesday, January 28, 2025 1/28/2025

Structural Studies of a T cell Specific Tyrosine Kinase

Award Number: R01AI043957
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary T cell development, activation, and differentiation are all dependent on TCR signaling, along with important contributions from costimulatory and cytokine receptor pathways. Many lines of evidence indicate that variations in TCR signal strength have a major impact on the outcome of these processes. For mature CD8 T cells, TCR signal strength determines proliferative capacity and effector versus memory potential following infection. We assert that there is a growing need to develop a more comprehensive understanding of the pathways regulating distinct T cell functions and differentiation processes. Moreover, manipulation of T cell responses underlies many therapeutic strategies currently in practice and under development. As this field has progressed, it has become clear there is a need for more nuanced manipulation of T cell signaling pathways. To achieve clinical efficacy, we need to understand how to tune T cell responses. The field presently lacks an understanding of how differences in TCR stimulation strength produce distinct gene expression patterns that steer T cell responses. We now have a body of data supporting a key role for the TEC kinase ITK in tuning T-cell signaling. ITK is not required for all TCR signaling; instead, in its absence, TCR signaling is significantly reduced. From these studies, the clear function of ITK has been difficult to discern, as some aspects of T cell activation appeared normal in the absence of ITK, whereas other T cell functions were greatly impaired. Our data now provide a framework to understand these apparent discrepancies, and suggest that variations in antigen density and in TCR affinity dictate the magnitude of ITK activity modulating subsequent gene expression responses. This proposal will study the contribution of specific ITK activation mechanisms (Aim 1) and costimulatory interactions (Aim 2) to understand how ITK mediates tunable responses to TCR stimulation. Biochemical and structural biology insights are directly transferred into primary T cell experiments to elucidate the molecular mechanisms controlling ITK regulation. We will also study the role of ITK regulation in human disease (Aim 3). Genetic mutations that activate ITK have been recently identified in patients with autoimmunity and there is evidence that the ITK-SYK fusion tyrosine kinase interacts with normal ITK in promoting oncogenesis in peripheral T cell lymphomas. The results of these studies will provide us with critical information about the nature of ITK regulation and how ITK activity influences T cell activation in response to TCR signal strength.


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 = $562,986 )
2024	2024	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Allergy and Infectious Diseases Research	000	26	7/5/2024	COMPETING CONTINUATION	$497,572
2024	2024	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Allergy and Infectious Diseases Research	001	26	9/3/2024	COMPETING CONTINUATION	$65,414
														Subtotal = $562,986

Issue Date FY: 2023 ( Subtotal = $451,729 )
2023	2023	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	515 MORRILL RD, 1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Allergy and Infectious Diseases Research	000	25	7/24/2023	NON-COMPETING CONTINUATION	$451,729
														Subtotal = $451,729

Issue Date FY: 2022 ( Subtotal = $452,013 )
2022	2022	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	515 MORRILL RD, 1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Allergy and Infectious Diseases Research	000	24	8/19/2022	NON-COMPETING CONTINUATION	$452,013
														Subtotal = $452,013

Issue Date FY: 2021 ( Subtotal = $452,256 )
2021	2021	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	515 MORRILL RD, 1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Allergy and Infectious Diseases Research	000	23	7/30/2021	NON-COMPETING CONTINUATION	$452,256
														Subtotal = $452,256

Issue Date FY: 2020 ( Subtotal = $452,486 )
2020	2020	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	515 MORRILL RD, 1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Allergy and Infectious Diseases Research	002	22	7/16/2020	NON-COMPETING CONTINUATION	$452,486
2020	2019	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	515 MORRILL RD, 1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Allergy and Infectious Diseases Research	001	21	5/19/2020	COMPETING CONTINUATION	$725
2020	2018	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	515 MORRILL RD, 1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Allergy and Infectious Diseases Research	000	20	5/19/2020	NON-COMPETING CONTINUATION	-$725
														Subtotal = $452,486

Issue Date FY: 2019 ( Subtotal = $479,209 )
2019	2019	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	515 MORRILL RD, 1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Allergy and Infectious Diseases Research	000	21	5/1/2019	COMPETING CONTINUATION	$479,209
														Subtotal = $479,209

Issue Date FY: 2018 ( Subtotal = $365,944 )
2018	2018	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Allergy and Infectious Diseases Research	000	20	8/15/2018	NON-COMPETING CONTINUATION	$365,944
														Subtotal = $365,944

Issue Date FY: 2017 ( Subtotal = $366,445 )
2017	2017	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Allergy and Infectious Diseases Research	000	19	8/3/2017	NON-COMPETING CONTINUATION	$366,445
														Subtotal = $366,445

Issue Date FY: 2016 ( Subtotal = $366,926 )
2016	2016	IOWA STATE UNIVERSITY OF SCIENCE & TECHNOLOGY	3609 ADMINISTRATIVE SVCS BLDG	AMES	IA	50011	STORY	USA	Allergy and Infectious Diseases Research	000	18	7/5/2016	NON-COMPETING CONTINUATION	$366,926
														Subtotal = $366,926

Issue Date FY: 2015 ( Subtotal = $361,894 )
2015	2015	IOWA STATE UNIVERSITY OF SCIENCE & TECHNOLOGY	3609 ADMINISTRATIVE SVCS BLDG	AMES	IA	50011	STORY	USA	Allergy and Infectious Diseases Research	000	17	7/27/2015	NON-COMPETING CONTINUATION	$361,894
														Subtotal = $361,894

Issue Date FY: 2014 ( Subtotal = $375,058 )
2014	2014	IOWA STATE UNIVERSITY OF SCIENCE & TECHNOLOGY	3609 ADMINISTRATIVE SVCS BLDG	AMES	IA	50011	STORY	USA	Allergy and Infectious Diseases Research	001	16	9/18/2014	COMPETING CONTINUATION	$375,058
2014	2013	IOWA STATE UNIVERSITY OF SCIENCE & TECHNOLOGY	3609 ADMINISTRATIVE SVCS BLDG	AMES	IA	50011	STORY	USA	Allergy and Infectious Diseases Research	000	15	9/12/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $375,058

Issue Date FY: 2013 ( Subtotal = $302,146 )
2013	2013	IOWA STATE UNIVERSITY OF SCIENCE & TECHNOLOGY	3609 ADMINISTRATIVE SVCS BLDG	AMES	IA	50011	STORY	USA	Allergy and Infectious Diseases Research	001	15	5/31/2013	NON-COMPETING CONTINUATION	$12,858
2013	2013	IOWA STATE UNIVERSITY OF SCIENCE & TECHNOLOGY	3609 ADMINISTRATIVE SVCS BLDG	AMES	IA	50011	STORY	USA	Allergy and Infectious Diseases Research	000	15	4/12/2013	NON-COMPETING CONTINUATION	$289,288
														Subtotal = $302,146

Issue Date FY: 2012 ( Subtotal = $321,693 )
2012	2012	IOWA STATE UNIVERSITY OF SCIENCE & TECHNOLOGY	3609 ADMINISTRATIVE SVCS BLDG	AMES	IA	50011	STORY	USA	Allergy and Infectious Diseases Research	000	14	4/12/2012	NON-COMPETING CONTINUATION	$321,693
														Subtotal = $321,693

Issue Date FY: 2011 ( Subtotal = $321,942 )
2011	2011	IOWA STATE UNIVERSITY OF SCIENCE & TECHNOLOGY	3609 ADMINISTRATIVE SVCS BLDG	AMES	IA	50011	STORY	USA	Allergy and Infectious Diseases Research	000	13	4/26/2011	NON-COMPETING CONTINUATION	$292,674
2011	2011	IOWA STATE UNIVERSITY OF SCIENCE & TECHNOLOGY	3609 ADMINISTRATIVE SVCS BLDG	AMES	IA	50011	STORY	USA	Allergy and Infectious Diseases Research	001	13	6/8/2011	NON-COMPETING CONTINUATION	$29,268
														Subtotal = $321,942

Issue Date FY: 2010 ( Subtotal = $325,431 )
2010	2010	IOWA STATE UNIVERSITY OF SCIENCE & TECHNOLOGY	3609 ADMINISTRATIVE SVCS BLDG	AMES	IA	50011	STORY	USA	Allergy and Infectious Diseases Research	000	12	4/26/2010	NON-COMPETING CONTINUATION	$325,431
														Subtotal = $325,431

Issue Date FY: 2009 ( Subtotal = $328,945 )
2009	2009	IOWA STATE UNIVERSITY OF SCIENCE & TECHNOLOGY	3609 ADMINISTRATIVE SVCS BLDG	AMES	IA	50011	STORY	USA	Allergy and Infectious Diseases Research	001	11	4/20/2009	COMPETING CONTINUATION	$328,945
2009	2008	IOWA STATE UNIVERSITY OF SCIENCE & TECHNOLOGY	3609 ADMINISTRATIVE SVCS BLDG	AMES	IA	50011	STORY	USA	Allergy and Infectious Diseases Research	000	10	4/20/2009	NON-COMPETING CONTINUATION	$0
														Subtotal = $328,945

Issue Date FY: 2008 ( Subtotal = $300,726 )
2008	2008	IOWA STATE UNIVERSITY OF SCIENCE & TECHNOLOGY	3609 ADMINISTRATIVE SVCS BLDG	AMES	IA	50011	STORY	USA	Allergy and Infectious Diseases Research	000	10	3/14/2008	NON-COMPETING CONTINUATION	$300,726
														Subtotal = $300,726

Issue Date FY: 2007 ( Subtotal = $306,739 )
2007	2007	IOWA STATE UNIVERSITY OF SCIENCE & TECHNOLOGY	3609 ADMINISTRATIVE SVCS BLDG	AMES	IA	50011	STORY	USA	Allergy and Infectious Diseases Research	000	9	4/2/2007	NON-COMPETING CONTINUATION	$306,739
														Subtotal = $306,739

Issue Date FY: 2006 ( Subtotal = $316,089 )
2006	2006	IOWA STATE UNIVERSITY OF SCIENCE & TECHNOLOGY	3609 ADMINISTRATIVE SVCS BLDG	AMES	IA	50011	STORY	USA	Allergy and Infectious Diseases Research	000	8	2/17/2006	NON-COMPETING CONTINUATION	$316,089
														Subtotal = $316,089

Issue Date FY: 2005 ( Subtotal = $323,880 )
2005	2005	IOWA STATE UNIVERSITY OF SCIENCE & TECHNOLOGY	309 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Allergy and Infectious Diseases Research	000	7	3/18/2005	NON-COMPETING CONTINUATION	$323,880
														Subtotal = $323,880

Issue Date FY: 2004 ( Subtotal = $322,577 )
2004	2004	IOWA STATE UNIVERSITY OF SCIENCE & TECHNOLOGY	309 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Allergy and Infectious Diseases Research	000	6	2/23/2004	COMPETING CONTINUATION	$322,577
														Subtotal = $322,577

Issue Date FY: 2003 ( Subtotal = $146,897 ) (Continued on the next page)
Grand Total All Awards = $8,541,040

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Structural Studies of a T cell Specific Tyrosine Kinase

Award Number: R01AI043957

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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