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Mechanistic relationships between IDO, GCN2, and mTOR signals in immunity to apoptotic cells

Award Number: R01AR067763
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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¿ DESCRIPTION (provided by applicant): The spleen is required for the generation of systemic tolerance to apoptotic cells. We have recently shown a specialized set of macrophages residing in the marginal zone region of the red pulp drive immunologic tolerance to apoptotic material and in their absence apoptotic cells induce inflammation and autoimmune reactivity. While it is not known how this occurs on a mechanistic level, we have found apoptotic cells provoke expression of a tryptophan-catabolizing enzyme, indoleamine 2, 3 dioxygenase (IDO), which is critical for immune suppression in a variety of inflammatory settings. Further we discovered blockade of IDO greatly altered the way macrophages and dendritic cells respond to apoptotic cells with increased inflammatory immunity and autoimmune disease activity in lupus-prone animals. Thus the data suggest a novel mechanism whereby IDO activity in macrophages controls both innate and adaptive immunity to apoptotic cells. Our proposed project will examine how apoptotic cells driven IDO activity impacts mTOR signals in marginal zone macrophages, how IDO-driven tryptophan metabolism impacts apoptotic cell-mediated tolerance, and mechanisms by which IDO may influence Treg activation; finally testing these mechanisms in an experimental model of systemic lupus erythematosus. Thus, the findings of this project could have enormous implications in diseases of hypo and hyper-immunity where modulation of the tolerogenic rheostat would provide significant clinical benefit.


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: 2021 ( Subtotal = $0 )
2021	2019	UNIVERSITY HEALTH NETWORK	200 ELIZABETH ST	TORONTO	ON			CAN	Arthritis, Musculoskeletal and Skin Diseases Research	000	6	8/25/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2019	UNIVERSITY HEALTH NETWORK	200 ELIZABETH ST	TORONTO	ON	M5G 2C4		CAN	Arthritis, Musculoskeletal and Skin Diseases Research	000	6	9/17/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $237,600 )
2019	2019	UNIVERSITY HEALTH NETWORK	200 ELIZABETH ST	TORONTO	ON	M5G 2C4		CAN	Arthritis, Musculoskeletal and Skin Diseases Research	000	6	4/1/2019	NON-COMPETING CONTINUATION	$237,600
														Subtotal = $237,600

Issue Date FY: 2018 ( Subtotal = $237,600 )
2018	2018	UNIVERSITY HEALTH NETWORK	200 ELIZABETH ST	TORONTO	ON	M5G 2C4		CAN	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	4/20/2018	NON-COMPETING CONTINUATION	$237,600
														Subtotal = $237,600

Issue Date FY: 2017 ( Subtotal = $237,600 )
2017	2017	UNIVERSITY HEALTH NETWORK	200 ELIZABETH ST	TORONTO	ON	M5G 2C4		CAN	Arthritis, Musculoskeletal and Skin Diseases Research	001	4	6/14/2017	NON-COMPETING CONTINUATION	$23,760
2017	2017	UNIVERSITY HEALTH NETWORK	200 ELIZABETH ST	TORONTO	ON	M5G 2C4		CAN	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	4/27/2017	NON-COMPETING CONTINUATION	$213,840
														Subtotal = $237,600

Issue Date FY: 2016 ( Subtotal = $198,317 )
2016	2016	UNIVERSITY HEALTH NETWORK	200 ELIZABETH STREET	TORONTO ONTARIO				CAN	Arthritis, Musculoskeletal and Skin Diseases Research	002	3	4/29/2016	NON-COMPETING CONTINUATION	$237,600
2016	2015	UNIVERSITY HEALTH NETWORK	200 ELIZABETH STREET	TORONTO ONTARIO				CAN	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	2/25/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$96,425
2016	2015	GEORGIA REGENTS RESEARCH INSTITUTE INC	1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Arthritis, Musculoskeletal and Skin Diseases Research	001	1	2/25/2016	NEW	-$135,708
														Subtotal = $198,317

Issue Date FY: 2015 ( Subtotal = $333,850 )
2015	2015	GEORGIA REGENTS RESEARCH INSTITUTE INC	1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	3/9/2015	NEW	$333,850
														Subtotal = $333,850

Grand Total All Awards = $1,244,967

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Mechanistic relationships between IDO, GCN2, and mTOR signals in immunity to apoptotic cells

Award Number: R01AR067763

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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