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Mechanisms of autoimmune disease risk in IL2/IL2RA-dependent immune tolerance

Award Number: R01AI154773
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: 02/23/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Mechanisms of autoimmune disease risk in IL2/IL2RA-dependent immune tolerance - Project Summary Interleukin-2 is a potent T cell growth factor with crucial roles in both immunity and self-tolerance. Genome-wide association studies (GWAS) in humans have shown that genetic variation at the IL2 and IL2RA loci influence susceptibility to multiple immune-mediated diseases including allergic asthma, systemic lupus erythematosus, and inflammatory bowel disease (IBD), identifying this as a key molecular axis that controls immune activity. However, mechanistic basis of disease risk for these polymorphisms is poorly understood. We have new evidence that the cis-regulatory architectures of IL2 and IL2RA extend much further from the gene than previously appreciated, encompassing regions harboring known disease-associated variants, and we hypothesize that polymorphisms within these elements control the level and timing of IL-2 and IL-2RA expression to control the balance of tolerance vs. inflammation. In this application, we propose a comprehensive screen for potential cis-regulatory elements that interact with the IL2 and IL2RA genes using state-of-the-art epigenomic approaches like ATAC-seq and Capture-C-seq. We will establish how these elements contribute to IL2 and IL2RA gene expression using powerful, CRISPR/CAS9-based genome editing approaches. To study the impact of disease-associated genetic variation at these regulatory elements on immune function in in vivo systems, we will analyze the responses of genetically characterized subjects curated from the Benaroya Research Institute biorepository, and create mice in which orthologous murine Il2 and Il2ra enhancer sequences have been replaced with human risk alleles, assessing the disease susceptibility in models of allergic asthma, SLE and IBD. Our studies will provide comprehensive maps of the transcriptional architecture of IL2 and IL2RA, insights into the molecular basis for the genetic association of IL2 and IL2RA with autoimmune disease, and may guide the design of new approaches for the treatment of organ transplant rejection and inflammatory disease.


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 = $0 )
2026	2025	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	5	11/7/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $731,602 )
2025	2025	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	5	1/15/2025	NON-COMPETING CONTINUATION	$731,602
														Subtotal = $731,602

Issue Date FY: 2024 ( Subtotal = $754,229 )
2024	2024	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	001	4	5/28/2024	NON-COMPETING CONTINUATION	$75,423
2024	2024	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	4	12/14/2023	NON-COMPETING CONTINUATION	$678,806
														Subtotal = $754,229

Issue Date FY: 2023 ( Subtotal = $754,229 )
2023	2023	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	3	1/11/2023	NON-COMPETING CONTINUATION	$754,229
														Subtotal = $754,229

Issue Date FY: 2022 ( Subtotal = $754,229 )
2022	2022	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	2	1/20/2022	NON-COMPETING CONTINUATION	$754,229
														Subtotal = $754,229

Issue Date FY: 2021 ( Subtotal = $773,229 )
2021	2021	CHILDREN'S HOSPITAL OF PHILADELPHIA, THE	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Allergy and Infectious Diseases Research	000	1	2/23/2021	NEW	$773,229
														Subtotal = $773,229

Grand Total All Awards = $3,767,518

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Mechanisms of autoimmune disease risk in IL2/IL2RA-dependent immune tolerance

Award Number: R01AI154773

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: 02/23/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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