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Molecular and Functional Analysis of Innate Immune Receptors

Award Number: R01AI029564
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: 07/01/1991
PERIOD OF PERFORMANCE END DATE: 04/30/2029

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Molecular and Functional Analysis of Innate Immune Receptors - PROJECT ABSTRACT One of the most important functions of innate immune receptors is the recognition of nucleic acids. Two key DNA binding receptors are the AIM2 (absent in melanoma) inflammasome and the cGAS (cyclic GMP-AMP synthase) protein. AIM2 is a member of the IFN-inducible HIN-200 family which is comprised of an N-terminal (pyrin) PYD and a C-terminal HIN-200 domain. Upon binding of DNA to the HIN-200 domain, the PYD is released to interact with the common inflammasome adaptor molecule, ASC (apoptoic speck containing protein with a CARD). This leads to the recruitment and activation of caspase-1, and the cleavage and maturation of IL-1, IL- 18 and the pyroptotic executioner, gasdermin D (GSDMD). AIM2 mediates inflammasome response to a wide range of bacterial, viral and self-derived DNA in a sequence-independent but length-dependent fashion. cGAS is a cytosolic enzyme that synthesizes a cyclic dinucleotide, cGAMP, from ATP and GTP. cGAMP in turn is recognized by the STING (stimulator of interferon genes) innate immune receptor, leading to the downstream activation of TBK1, NFB and IRF3 which cumulate in the transcriptional activation of type I interferon and numerous inflammatory cytokines. While much is known about the functional roles of these two molecules, critical knowledge remains missing. For example, limited information is available on the structure of DNA that is recognized by these molecules in myeloid cells. New preliminary findings lead us to hypothesize that the secondary structure of nucleic acids impacts their recognition and likely functional outcomes. Aim 1 will test this hypothesis. Another critical knowledge that is understudied centers on the roles of these innate immune receptors in adaptive immune cells. Innate immune receptors have been primarily studied in myeloid cells, however an analysis of their expression indicates that many are well expressed by adaptive T and B lymphocytes. We have recently shown that both AIM2 and STING play prominent and surprising roles in T and B cells. We find that AIM2 promotes T regulatory (Treg) cells in vitro and in vivo and this is due to the association of AIM2 with the RACK1 kinase and PP2a phosphatase complex, which then blocks Akt activation. We also unexpectedly found that STING induces an IL-35/IL-10 phenotype in B cells with markers and functions that are consistent with B regulatory cells. The relevance of these innate immune receptors in lymphocytes will be the focus of this proposal.


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: 2026 ( Subtotal = $571,581 )
2026	2026	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	000	33	5/12/2026	NON-COMPETING CONTINUATION	$571,581
														Subtotal = $571,581

Issue Date FY: 2025 ( Subtotal = $571,581 )
2025	2025	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	001	32	5/1/2025	NON-COMPETING CONTINUATION	$571,581
2025	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	000	30	2/24/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $571,581

Issue Date FY: 2024 ( Subtotal = $555,737 )
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	002	31	9/4/2024	COMPETING CONTINUATION	$55,574
2024	2024	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	001	31	6/5/2024	COMPETING CONTINUATION	$500,163
2024	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	000	30	6/4/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $555,737

Issue Date FY: 2022 ( Subtotal = $502,378 )
2022	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	000	30	5/19/2022	NON-COMPETING CONTINUATION	$502,378
														Subtotal = $502,378

Issue Date FY: 2021 ( Subtotal = $502,378 )
2021	2021	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	000	29	5/24/2021	NON-COMPETING CONTINUATION	$502,378
														Subtotal = $502,378

Issue Date FY: 2020 ( Subtotal = $502,378 )
2020	2020	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	000	28	7/16/2020	NON-COMPETING CONTINUATION	$502,378
														Subtotal = $502,378

Issue Date FY: 2019 ( Subtotal = $502,378 )
2019	2019	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	000	27	5/31/2019	NON-COMPETING CONTINUATION	$502,378
														Subtotal = $502,378

Issue Date FY: 2018 ( Subtotal = $502,407 )
2018	2018	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	001	26	8/21/2018	COMPETING CONTINUATION	$29
2018	2018	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	000	26	5/28/2018	COMPETING CONTINUATION	$502,378
														Subtotal = $502,407

Issue Date FY: 2005 ( Subtotal = $326,074 )
2005	2005	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	000	15	5/9/2005	NON-COMPETING CONTINUATION	$326,074
														Subtotal = $326,074

Issue Date FY: 2004 ( Subtotal = $326,074 )
2004	2004	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	000	14	5/17/2004	NON-COMPETING CONTINUATION	$326,074
														Subtotal = $326,074

Issue Date FY: 2003 ( Subtotal = $326,074 )
2003	2003	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	000	13		NON-COMPETING CONTINUATION	$326,074
														Subtotal = $326,074

Issue Date FY: 2002 ( Subtotal = $326,074 )
2002	2002	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	000	12	6/15/2002	NON-COMPETING CONTINUATION	$326,074
														Subtotal = $326,074

Issue Date FY: 2001 ( Subtotal = $293,466 )
2001	2001	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	000	11	9/4/2001	COMPETING CONTINUATION	$293,466
														Subtotal = $293,466

Issue Date FY: 2000 ( Subtotal = $237,549 )
2000	2000	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	000	10	8/4/2000	NON-COMPETING CONTINUATION	$237,549
														Subtotal = $237,549

Issue Date FY: 1999 ( Subtotal = $228,480 )
1999	1999	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	000	9	4/29/1999	NON-COMPETING CONTINUATION	$228,480
														Subtotal = $228,480

Issue Date FY: 1998 ( Subtotal = $219,762 )
1998	1998	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Allergy and Infectious Diseases Research	000	8	3/23/1998	NON-COMPETING CONTINUATION	$219,762
														Subtotal = $219,762

Grand Total All Awards = $6,494,371

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Molecular and Functional Analysis of Innate Immune Receptors

Award Number: R01AI029564

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: 07/01/1991

PERIOD OF PERFORMANCE END DATE: 04/30/2029

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