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The cell and molecular mechanisms underlying CD28 costimulation

Award Number: R37AI114575
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2015
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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The cell and molecular mechanisms underlying CD28 costimulation - CD28 is a T cell surface molecule that can provide a second signal, when combined with immobilized TCR ligands, to induce naïve T activation. Costimulation results from the interaction of CD28 with its ligands CD80 (B7.1) and CD86 (B7.2) induced on activated antigen-presenting cells by activation of the innate immune system. We do not have a good molecular understanding of how CD28 mediates its costimulatory signals. Models and experimental evidence have suggested that CD28 either: 1) augments the magnitude of TCR signaling; or, 2) provides a unique signal, qualitatively distinct from that provided by the TCR. It is important to understand the molecular signaling pathways underlying costimulation since interrupting costimulation has been important clinically. A deeper insight into CD28 signaling pathways may enable the development of new therapeutics that would be useful in blocking the immune system. Very recent studies from my lab provide some new insights and suggest approaches and clues that will enable us identify previously unrecognized components of the CD28-regulated signaling pathways and permit a more complete understanding of CD28 signaling. These chemical-biology, genetic and proteomic studies lead us to hypothesize that an important consequence of CD28 costimulation is the regulation of the actin cytoskeleton and this influences signals downstream of the TCR. We will explore this via the following specific aims: 1) Determine the mechanism by which costimulation modulates the actin cytoskeleton to facilitate PLCγ1 mediated hydrolysis of PIP2 in double positive (CD4+CD8+, DP) thymocytes and in more mature T cells; 2) Determine how CD28 overcomes a negative regulatory influence of Pyk2 and Cbl-b on T cell signaling leading to IL-2 production and T cell proliferation; and, 3) Using recently obtained phosphoproteomic data, we will identify key components of the pathway downstream of CD28 and those that modulate the actin cytoskeleton in response to CD28 costimulation.


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: 2023 ( Subtotal = $403,750 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	8	11/7/2022	NON-COMPETING CONTINUATION	$403,750
														Subtotal = $403,750

Issue Date FY: 2022 ( Subtotal = $403,750 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	7	12/3/2021	NON-COMPETING CONTINUATION	$403,750
														Subtotal = $403,750

Issue Date FY: 2021 ( Subtotal = $403,750 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	002	6	7/26/2021	EXTENSION WITH OR WITHOUT FUNDS	$34,273
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	6	11/27/2020	EXTENSION WITH OR WITHOUT FUNDS	$403,750
2021	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	001	5	7/26/2021	NON-COMPETING CONTINUATION	-$34,273
														Subtotal = $403,750

Issue Date FY: 2020 ( Subtotal = $396,250 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	5	11/18/2019	NON-COMPETING CONTINUATION	$396,250
														Subtotal = $396,250

Issue Date FY: 2019 ( Subtotal = $396,250 )
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	4	11/26/2018	NON-COMPETING CONTINUATION	$396,250
														Subtotal = $396,250

Issue Date FY: 2018 ( Subtotal = $396,250 )
2018	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 420	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	3	11/24/2017	NON-COMPETING CONTINUATION	$396,250
														Subtotal = $396,250

Issue Date FY: 2017 ( Subtotal = $396,250 )
2017	2017	UNIVERSITY OF CALIFORNIA, SAN FRANCISCO	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	2	11/18/2016	NON-COMPETING CONTINUATION	$396,250
														Subtotal = $396,250

Issue Date FY: 2016 ( Subtotal = $396,250 )
2016	2016	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Allergy and Infectious Diseases Research	000	1	12/8/2015	NEW	$396,250
														Subtotal = $396,250

Grand Total All Awards = $3,192,500

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The cell and molecular mechanisms underlying CD28 costimulation

Award Number: R37AI114575

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2015

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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