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CRAC Channel Deficiency in Immunity to Infection

Award Number: R01AI097302
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: 06/01/2012
PERIOD OF PERFORMANCE END DATE: 04/30/2024

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CRAC Channel Deficiency in Immunity to Infection - Summary The goal of our research is to understand how defects in calcium influx in cells of the immune system cause immunodeficiency in patients with inherited mutations in genes regulating calcium influx. Since the same patients also suffer from anemia caused by autoantibodies against red blood cells, a second goal of our research is to understand how calcium influx maintains immunological self-tolerance and prevents autoimmunity. Our central hypothesis is that CRAC channels, which mediate calcium influx across the cell membrane, are required for the function of different cells in the innate and adaptive arms of the immune system that provide immunity to infection and prevent autoimmunity. CRAC channels are the main source of calcium influx in most immune cells. They are formed by the channel protein ORAI1 and are activated by STIM1 and STIM2. We have identified the first patients with mutations in ORAI1 and STIM1 genes who suffer from a disease we called CRAC channelopathy that is characterized by immunodeficiency, autoimmunity, and several non-immunological defects. Because CRAC channelopathy is a rare disease and patient samples are limited, we generated mice that lack CRAC channels in T cells. By investigating immune responses in these mice and by validating key results in samples of patients with CRAC channelopathy, we have been able to define a critical role of CRAC channels in T cell-mediated immune responses, in particular for cellular and antibody-mediated immunity to infection and for limiting immune responses during chronic infection that would otherwise cause harmful inflammation. However, we are still far from having a complete picture of how CRAC channels regulate immunity to infection. Beyond T cells, CRAC channels may also regulate innate immune responses mediated by dendritic cells and neutrophils. Studies so far have yielded conflicting data whether CRAC channels are required for innate immune cell function, and their role for innate immunity to infection has not been studied. Besides immunity to infection, CRAC channels are essential for immunological self-tolerance by controlling the development of regulatory T cells, which suppress the function of other immune cells and thereby prevent autoimmunity. CRAC channel-deficient patients have fewer Treg cells, potentially explaining their autoimmunity. How CRAC channels control the function of Treg cells and prevent autoimmunity is not understood. To address these questions, we propose the following three specific aims: (1) We will analyze inherited defects in ORAI1 and STIM1 genes of patients to understand the role of CRAC channels for immune function and the molecular regulation of CRAC channels. (2) We will determine if CRAC channels are required for innate immune responses by dendritic cells and neutrophils to fight bacterial and fungal infections. (3) We will determine how CRAC channels control regulatory T cell function and prevent autoimmunity, in particular autoimmune hemolytic anemia, by studying CRAC channel-deficient mice and patients. Our studies will provide fundamental insights how CRAC channels regulate immunity to infection and prevent autoimmunity.


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 = $0 )
2025	2022	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Allergy and Infectious Diseases Research	000	10	11/22/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $541,293 )
2022	2022	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Allergy and Infectious Diseases Research	000	10	4/27/2022	NON-COMPETING CONTINUATION	$541,293
														Subtotal = $541,293

Issue Date FY: 2021 ( Subtotal = $541,293 )
2021	2021	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Allergy and Infectious Diseases Research	000	9	4/21/2021	NON-COMPETING CONTINUATION	$541,293
														Subtotal = $541,293

Issue Date FY: 2020 ( Subtotal = $541,293 )
2020	2020	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Allergy and Infectious Diseases Research	000	8	3/27/2020	NON-COMPETING CONTINUATION	$541,293
														Subtotal = $541,293

Issue Date FY: 2019 ( Subtotal = $536,208 )
2019	2019	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Allergy and Infectious Diseases Research	000	7	4/18/2019	NON-COMPETING CONTINUATION	$536,208
														Subtotal = $536,208

Issue Date FY: 2018 ( Subtotal = $536,208 )
2018	2018	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Allergy and Infectious Diseases Research	001	6	5/14/2018	COMPETING CONTINUATION	$536,208
2018	2018	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Allergy and Infectious Diseases Research	003	6	9/25/2018	COMPETING CONTINUATION	$241,482
2018	2017	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Allergy and Infectious Diseases Research	000	5	5/9/2018	NON-COMPETING CONTINUATION	$0
2018	2017	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Allergy and Infectious Diseases Research	002	5	9/25/2018	NON-COMPETING CONTINUATION	-$241,482
														Subtotal = $536,208

Issue Date FY: 2017 ( Subtotal = $481,296 )
2017	2017	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Allergy and Infectious Diseases Research	001	5	5/15/2017	NON-COMPETING CONTINUATION	$486,036
2017	2015	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Allergy and Infectious Diseases Research	000	3	11/15/2016	NON-COMPETING CONTINUATION	$0
2017	2013	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	HHS Programs for Disaster Relief Appropriations Act - Non Construction	002	2	6/5/2017	SUPPLEMENT FOR EXPANSION	-$4,740
														Subtotal = $481,296

Issue Date FY: 2016 ( Subtotal = $486,036 )
2016	2016	NEW YORK UNIVERSITY MEDICAL CENTER	550 1ST AVE, SC-2 KIPS BAY BG	NEW YORK	NY	10016	NEW YORK	USA	Allergy and Infectious Diseases Research	000	4	5/12/2016	EXTENSION WITH OR WITHOUT FUNDS	$486,036
														Subtotal = $486,036

Issue Date FY: 2015 ( Subtotal = $486,036 )
2015	2015	NEW YORK UNIVERSITY MEDICAL CENTER	550 1ST AVE, SC-2 KIPS BAY BG	NEW YORK	NY	10016	NEW YORK	USA	Allergy and Infectious Diseases Research	001	3	5/5/2015	NON-COMPETING CONTINUATION	$486,036
2015	2013	NEW YORK UNIVERSITY MEDICAL CENTER	550 1ST AVE, SC-2 KIPS BAY BG	NEW YORK	NY	10016	NEW YORK	USA	HHS Programs for Disaster Relief Appropriations Act - Non Construction	000	2	3/19/2015	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $486,036

Issue Date FY: 2014 ( Subtotal = $89,528 )
2014	2014	NEW YORK UNIVERSITY MEDICAL CENTER	550 1ST AVE, SC-2 KIPS BAY BG	NEW YORK	NY	10016	NEW YORK	USA	Allergy and Infectious Diseases Research	000	2	8/14/2014	SUPPLEMENT FOR EXPANSION	$89,528
														Subtotal = $89,528

Issue Date FY: 2013 ( Subtotal = $913,741 )
2013	2013	NEW YORK UNIVERSITY MEDICAL CENTER	550 1ST AVE, SC-2 KIPS BAY BG	NEW YORK	NY	10016	NEW YORK	USA	Allergy and Infectious Diseases Research	000	2	5/7/2013	NON-COMPETING CONTINUATION	$456,871
2013	2013	NEW YORK UNIVERSITY MEDICAL CENTER	550 1ST AVE, SC-2 KIPS BAY BG	NEW YORK	NY	10016	NEW YORK	USA	Allergy and Infectious Diseases Research	002	2	8/20/2013	NON-COMPETING CONTINUATION	$0
2013	2013	NEW YORK UNIVERSITY MEDICAL CENTER	550 1ST AVE, SC-2 KIPS BAY BG	NEW YORK	NY	10016	NEW YORK	USA	HHS Programs for Disaster Relief Appropriations Act - Non Construction	001	2	8/19/2013	SUPPLEMENT FOR EXPANSION	$456,870
														Subtotal = $913,741

Issue Date FY: 2012 ( Subtotal = $486,036 )
2012	2012	NEW YORK UNIVERSITY MEDICAL CENTER	550 1ST AVE, SC-2 KIPS BAY BG	NEW YORK	NY	10016	NEW YORK	USA	Allergy and Infectious Diseases Research	000	1	5/22/2012	NEW	$486,036
														Subtotal = $486,036

Grand Total All Awards = $5,638,968

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CRAC Channel Deficiency in Immunity to Infection

Award Number: R01AI097302

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: 06/01/2012

PERIOD OF PERFORMANCE END DATE: 04/30/2024

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