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Dissect and target Arginine-polyamine metabolic axis in T cell mediated inflammation and autoimmunity

Award Number: R01AI114581
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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1 Summary: 2 CD4 T cell activation provides a model system for studying molecular mechanisms that coordinate a wide variety 3 of often competing physiological processes. When CD4 T cells encounter an antigen in the proper context, they 4 rapidly accumulate biomass, undergo extensive expansion, and differentiate into functional lineages that spe- 5 cialize on cytokine production. Robust and effective CD4 T cell-mediated immune responses require proper al- 6 location of metabolic resources through the central carbon metabolic pathways to sustain energetically costly 7 processes like growth, proliferation, and cytokine production. Also, ancillary metabolic pathways, such as amino 8 acid catabolism and polyamine (PA) biosynthesis, are critical to regulating T cell proliferation and inflammation. 9 The objective of this proposal is to understand how the arginine-polyamine metabolic axis is regulated during 10 T cell activation and ultimately contributes to inflammation and autoimmunity. Our lab recently revealed that the 11 transcription factor, c-Myc, controls an ancillary metabolic pathway that connects arginine (Arg) catabolism to 12 the biosynthesis of PAs, which are an essential class of polycationic metabolites ubiquitously present in all living 13 organisms. Unlike most other amino acids that are primarily used for anabolic protein synthesis during T cell 14 activation, most cellular Arg is catabolized and funneled into synthesizing PA (Arg-PA metabolic axis). Genetic 15 and pharmacological perturbation in the intracellular PA pool suppresses proliferation, suppresses TH1 and TH17 16 differentiation, but enhances iTreg differentiation. Hence, we hypothesize that the arginine-polyamine metabolic 17 axis orchestrates a metabolic checkpoint to optimize CD4 Teff cell proliferation and inflammatory re- 18 sponse. This checkpoint may be therapeutically exploited by polyamine blocking therapies. The aims of 19 this proposal are to 1) decipher the Arg-PA metabolic axis reprogramming and assess the impact of crucial 20 metabolic steps on Teff cells in the context of modulating Myc; 2) determine the outcomes of modulating Arg-PA 21 axis in regulating the effector function of T cells; 3) assess the contribution of PA de novo biosynthesis and the 22 PA salvage pathway to the intracellular PA-pool and T cell proliferation and effector function, and 4) develop and 23 test complementary enzymatic, genetic, and dietary strategies to exploit the Arg-PA axis to modulate inflamma- 24 tory response and autoimmunity in animal models of multiple sclerosis and rheumatoid arthritis. Collectively, the 25 expected outcomes of this project are significant as it will reveal the fundamental principles of the emerging 26 connections between cell metabolism, immune signaling, and T cell differentiation. These studies are critical to 27 developing novel approaches and therapeutic interventions that improve clinical outcomes of inflammatory and 28 autoimmune diseases.


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 = $348,075 )
2024	2024	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Allergy and Infectious Diseases Research	000	9	2/9/2024	NON-COMPETING CONTINUATION	$348,075
														Subtotal = $348,075

Issue Date FY: 2023 ( Subtotal = $386,750 )
2023	2023	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Allergy and Infectious Diseases Research	000	8	2/13/2023	NON-COMPETING CONTINUATION	$386,750
														Subtotal = $386,750

Issue Date FY: 2022 ( Subtotal = $386,750 )
2022	2022	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Allergy and Infectious Diseases Research	002	7	3/9/2022	NON-COMPETING CONTINUATION	$386,750
2022	2021	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Allergy and Infectious Diseases Research	001	6	11/2/2021	COMPETING CONTINUATION	$1
2022	2019	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Allergy and Infectious Diseases Research	000	5	11/2/2021	NON-COMPETING CONTINUATION	-$1
														Subtotal = $386,750

Issue Date FY: 2021 ( Subtotal = $400,250 )
2021	2021	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Allergy and Infectious Diseases Research	000	6	4/2/2021	COMPETING CONTINUATION	$400,250
														Subtotal = $400,250

Issue Date FY: 2019 ( Subtotal = $373,750 )
2019	2019	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Allergy and Infectious Diseases Research	000	5	2/11/2019	NON-COMPETING CONTINUATION	$373,750
														Subtotal = $373,750

Issue Date FY: 2018 ( Subtotal = $373,750 )
2018	2018	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Allergy and Infectious Diseases Research	000	4	2/17/2018	NON-COMPETING CONTINUATION	$373,750
														Subtotal = $373,750

Issue Date FY: 2017 ( Subtotal = $373,750 )
2017	2017	RESEARCH INSTITUTE AT NATIONWIDE CHILDREN'S HOSPITAL	700 CHILDRENS DR	COLUMBUS	OH	43205	FRANKLIN	USA	Allergy and Infectious Diseases Research	000	3	2/17/2017	NON-COMPETING CONTINUATION	$373,750
														Subtotal = $373,750

Issue Date FY: 2016 ( Subtotal = $373,750 )
2016	2016	Research Institute at Nationwide`s Children`s Hospital	700 CHILDREN`S DRIVE	COLUMBUS	OH	43205	FRANKLIN	USA	Allergy and Infectious Diseases Research	000	2	2/15/2016	NON-COMPETING CONTINUATION	$373,750
														Subtotal = $373,750

Issue Date FY: 2015 ( Subtotal = $186,875 )
2015	2015	Research Institute at Nationwide`s Children`s Hospital	700 CHILDREN`S DRIVE	COLUMBUS	OH	43205	FRANKLIN	USA	Allergy and Infectious Diseases Research	001	1	9/21/2015	NEW	$0
2015	2015	Research Institute at Nationwide`s Children`s Hospital	700 CHILDREN`S DRIVE	COLUMBUS	OH	43205	FRANKLIN	USA	Allergy and Infectious Diseases Research	000	1	8/7/2015	NEW	$186,875
														Subtotal = $186,875

Grand Total All Awards = $3,203,700

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Dissect and target Arginine-polyamine metabolic axis in T cell mediated inflammation and autoimmunity

Award Number: R01AI114581

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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