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Treg development and function controlled by cis-regulatory circuits

Award Number: R01AI107027
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: 01/01/2014
PERIOD OF PERFORMANCE END DATE: 12/31/2022

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Treg development and function controlled by cis-regulatory circuits - Project Summary Regulatory T cell (Treg) plays a critical role in maintaining immune system homeostasis and preventing autoimmunity and immunopathology. Compromised Treg function is linked to multiple autoimmune diseases including type 1 diabetes and multiple sclerosis. On the flip side, enrichment of Treg cells within tumors is thought to be a barrier to effective anti-tumor immune response. The development and maintenance of Treg cell lineage are dependent on transcription factor Foxp3, as loss of function mutations lead to severe lymphoproliferative disease in mice and humans. Thus, understanding the mechanisms that govern Foxp3 induction and stability may lead to the development of novel therapies for autoimmune disease and cancer. Previously, Dr. Zheng and colleagues identified three evolutionarily conserved cis-regulatory elements at the Foxp3 locus, which play unique roles in Treg differentiation or maintenance. To expand this line of research, Dr. Zheng’s group will use a CRISPR/Cas9 based approach named CREST-seq (cis-regulatory element scan by tiling-deletion and sequencing) to perform unbiased screen and functional assessment for distal cis-elements near the Foxp3 locus. A preliminary study showed there are potentially up to 50 cis-regulatory elements involved in the control of Foxp3 expression. In-depth characterization of these new cis-elements will advance the understandings on the regulatory circuitry of Foxp3 expression. Numerous studies generated annotations on millions of candidate regulatory elements for thousands of genes in Tregs, but understanding is incomplete on how these elements control their target genes that are kilo-bases or even mega-bases away. Preliminary studies on genome-wide chromosome looping in Tregs generated a collection of distal DNA loops that can potentially regulate Treg signature genes. Furthermore, these data suggest a novel role for Foxp3 in facilitating distal DNA looping. To better understand how cis-regulatory circuitry control Treg differentiation and function, Dr. Zheng’s group will identify and characterize the cis-elements that control Foxp3 expression by a tiling deletion based genetic screen (Aim 1) and explore how distal enhancers regulate gene expression in regulatory T cell through chromosome looping (Aim 2). Furthermore, they will investigate if Foxp3 facilitates chromosome looping to establish and maintain the Treg lineage. Since Treg cell is directly related to autoimmune diseases and cancer, Dr. Zheng’s study will provide insight into the molecular mechanisms of Treg development and function and offer new opportunities to manipulate Tregs for therapeutic purposes.


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: 2023 ( Subtotal = $0 )
2023	2022	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	9	9/18/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $648,013 )
2022	2022	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	9	12/20/2021	NON-COMPETING CONTINUATION	$648,013
														Subtotal = $648,013

Issue Date FY: 2021 ( Subtotal = $648,013 )
2021	2021	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	8	12/14/2020	NON-COMPETING CONTINUATION	$648,013
														Subtotal = $648,013

Issue Date FY: 2020 ( Subtotal = $648,013 )
2020	2020	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	7	1/31/2020	NON-COMPETING CONTINUATION	$648,013
														Subtotal = $648,013

Issue Date FY: 2019 ( Subtotal = $648,013 )
2019	2019	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	6	12/28/2018	COMPETING CONTINUATION	$648,013
2019	2019	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	002	6	6/21/2019	COMPETING CONTINUATION	$0
2019	2018	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	5	5/10/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $648,013

Issue Date FY: 2018 ( Subtotal = $485,000 )
2018	2018	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	5	12/26/2017	NON-COMPETING CONTINUATION	$485,000
														Subtotal = $485,000

Issue Date FY: 2017 ( Subtotal = $485,000 )
2017	2017	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	4	12/21/2016	NON-COMPETING CONTINUATION	$485,000
														Subtotal = $485,000

Issue Date FY: 2016 ( Subtotal = $485,000 )
2016	2016	SALK INSTITUTE FOR BIOLOGICAL STUDIES	P.O. BOX 85800	SAN DIEGO	CA	92186	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	3	12/17/2015	NON-COMPETING CONTINUATION	$485,000
														Subtotal = $485,000

Issue Date FY: 2015 ( Subtotal = $485,000 )
2015	2015	SALK INSTITUTE FOR BIOLOGICAL STUDIES	P.O. BOX 85800	SAN DIEGO	CA	92186	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	2	11/24/2014	NON-COMPETING CONTINUATION	$485,000
														Subtotal = $485,000

Issue Date FY: 2014 ( Subtotal = $485,000 )
2014	2014	SALK INSTITUTE FOR BIOLOGICAL STUDIES	P.O. BOX 85800	SAN DIEGO	CA	92186	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	1	12/18/2013	NEW	$436,500
2014	2014	SALK INSTITUTE FOR BIOLOGICAL STUDIES	P.O. BOX 85800	SAN DIEGO	CA	92186	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	1	6/9/2014	NEW	$48,500
														Subtotal = $485,000

Grand Total All Awards = $5,017,052

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Treg development and function controlled by cis-regulatory circuits

Award Number: R01AI107027

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: 01/01/2014

PERIOD OF PERFORMANCE END DATE: 12/31/2022

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