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MicroRNA directed pathway discovery in allergy and asthma

Award Number: R01HL109102
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2011
PERIOD OF PERFORMANCE END DATE: 02/28/2029

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MicroRNA directed pathway discovery in allergy and asthma - PROJECT SUMMARY Asthma is a highly prevalent chronic inflammatory airway disease that is genetically and mechanistically linked to allergy and dysregulated cytokine-mediated communication between the airway epithelial barrier and tissue-infiltrating immune cells. Th2 responses, insufficiently checked by Tregs, drive chronic allergic inflammation through the release of cytokines that signal through STAT6. Discovering novel regulatory circuits that control this process is a research opportunity with high promise for therapeutic application. In the proposed research, we will investigate RNA circuits that regulate Treg function and the pathobiology of allergy and asthma. Strong preliminary data implicate specific microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and mRNA cis-regulatory sequences as nodes in critical circuits that impact asthma incidence and pathogenesis. The proposed work is organized into 2 scientific aims. Aim 1 focuses on a circuit composed of the abundant miRNA family miR-15/16, its large network of target mRNAs, and the lncRNA MALAT1. miR-15/16 is required in Tregs to safeguard their suppressive function and inhibit allergic lung inflammation. We will functionally characterize the empirically determined target network of miR-15/16 in Tregs, and investigate the role of miR-15/16 interaction with MALAT1. Both miR-15/16 and Malat1 are extremely abundant in T cells, and their physical interaction prevents miR-15/16 from fully suppressing its coding gene targets. We will test the importance of this interaction in allergic lung inflammation using novel transgenic mice with a precise CRISPR-mediated mutation in the miR-15/16 interaction site. Aim 2 probes the biological functions of noncoding mRNA sequences implicated in asthma susceptibility by genetic studies, and implicated as cis-regulatory elements involved in RNA regulation by their association with RNA binding proteins. This work is guided by GCLiPP, a biochemical technique that we developed to map RNA:protein interactions transcriptome-wide. We will interrogate the function of protein-occupied RNA cis-regulatory elements through GCLiPP- directed CRISPR dissection, and conduct a deep analysis of cis-regulatory elements in the STAT6 3’ UTR using conventional reporter assays and CRISPR-directed base editing technology. If successful, the proposed research will illuminate novel RNA regulatory circuits active in allergy and asthma immunopathogenesis, and supply mechanistic insights to their molecular functions.


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 = $485,353 )
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Lung Diseases Research	000	15	4/6/2026	NON-COMPETING CONTINUATION	$485,353
														Subtotal = $485,353

Issue Date FY: 2025 ( Subtotal = $495,259 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Lung Diseases Research	001	14	4/22/2025	COMPETING CONTINUATION	$495,259
2025	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Lung Diseases Research	000	13	11/25/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $495,259

Issue Date FY: 2023 ( Subtotal = $418,794 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Lung Diseases Research	001	13	7/19/2023	SUPPLEMENT FOR EXPANSION	$15,044
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Lung Diseases Research	000	13	7/17/2023	NON-COMPETING CONTINUATION	$403,750
														Subtotal = $418,794

Issue Date FY: 2022 ( Subtotal = $482,116 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Lung Diseases Research	000	12	7/26/2022	NON-COMPETING CONTINUATION	$403,750
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Lung Diseases Research	001	12	8/23/2022	SUPPLEMENT FOR EXPANSION	$78,366
														Subtotal = $482,116

Issue Date FY: 2021 ( Subtotal = $403,750 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Lung Diseases Research	000	11	6/17/2021	NON-COMPETING CONTINUATION	$403,750
														Subtotal = $403,750

Issue Date FY: 2020 ( Subtotal = $403,750 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Lung Diseases Research	000	10	6/30/2020	COMPETING CONTINUATION	$403,750
2020	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Lung Diseases Research	001	9	9/22/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $403,750

Issue Date FY: 2019 ( Subtotal = $317,000 )
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Lung Diseases Research	000	9	3/28/2019	NON-COMPETING CONTINUATION	$317,000
														Subtotal = $317,000

Issue Date FY: 2018 ( Subtotal = $317,000 )
2018	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 420	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Lung Diseases Research	000	8	5/24/2018	NON-COMPETING CONTINUATION	$317,000
														Subtotal = $317,000

Issue Date FY: 2017 ( Subtotal = $317,000 )
2017	2017	UNIVERSITY OF CALIFORNIA, SAN FRANCISCO	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Lung Diseases Research	000	7	3/28/2017	NON-COMPETING CONTINUATION	$317,000
														Subtotal = $317,000

Issue Date FY: 2016 ( Subtotal = $317,000 )
2016	2016	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Lung Diseases Research	000	6	5/24/2016	COMPETING CONTINUATION	$317,000
														Subtotal = $317,000

Issue Date FY: 2015 ( Subtotal = $275,187 )
2015	2015	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Lung Diseases Research	000	5	7/1/2015	NON-COMPETING CONTINUATION	$275,187
														Subtotal = $275,187

Issue Date FY: 2014 ( Subtotal = $273,792 )
2014	2014	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Lung Diseases Research	000	4	6/13/2014	NON-COMPETING CONTINUATION	$273,792
														Subtotal = $273,792

Issue Date FY: 2013 ( Subtotal = $228,568 )
2013	2013	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Lung Diseases Research	000	3	7/5/2013	NON-COMPETING CONTINUATION	$228,568
														Subtotal = $228,568

Issue Date FY: 2012 ( Subtotal = $180,051 )
2012	2012	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Lung Diseases Research	000	2	7/17/2012	NON-COMPETING CONTINUATION	$180,051
														Subtotal = $180,051

Issue Date FY: 2011 ( Subtotal = $540,944 )
2011	2011	UNIVERSITY OF CALIFORNIA-SAN FRANCISCO	BOX 0812	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Lung Diseases Research	000	1	7/29/2011	NEW	$540,944
														Subtotal = $540,944

Grand Total All Awards = $5,455,564

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MicroRNA directed pathway discovery in allergy and asthma

Award Number: R01HL109102

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2011

PERIOD OF PERFORMANCE END DATE: 02/28/2029

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