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Chromosome 17q21, allergic inflammation, and remodeling

Award Number: R01AI107779
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: 05/15/2013
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Chromosome 17q21, allergic inflammation, and remodeling - The focus of this proposal is on ORMDL3 a gene on chromosome 17q21, which has been highly linked to human asthma in several genome wide association studies. As ORMDL3 is highly expressed in CD4+ cells, in this proposal we seek to determine how ORMDL3 influences CD4+ cell function, allergic inflammation, and asthma. Although the linkage of chromosome 17q21 to asthma is very well established, the biologic mechanism(s) underpinning this association in lung cells pertinent to the pathogenesis of asthma is not as well understood and is the focus of this proposal. In addition as there are at least 9 genes located in this region on chromosome 17q21 understanding the biology of each of these genes individually is important to understanding how this region influences the development of asthma. As the SNP linking ORMDL3 to asthma is associated with increased levels of ORMDL3 expression, we generated universal ORMDL3 transgenic (TG) mice that express increased levels of human ORMDL3 (hORMDL3) and demonstrated that they spontaneously (in the absence of allergen exposure) develop significantly increased ASM and increased AHR, major features of asthma. In addition to this important baseline effect of ORMDL3 in ASM on AHR, ORMDL3 also plays a significant role in enhancing Th2 responses and AHR as demonstrated in our studies of allergen challenged universal hORMDL3 TG mice. Thus, the focus of this proposal is to increase our understanding of how ORMDL3 expressed in CD4+ T lymphocytes enhances Th2 responses to allergen challenge. In this grant proposal we propose to demonstrate that CD4+ cells (mouse and human) expressing increased levels of ORMDL3 have enhanced Th2 responses in vitro and in vivo to house dust mite (HDM) allergen, and using proteomic and RNAseq approaches plan to identify downstream pathways in HDM tetramer positive CD4+ cells that mediate this ORMDL3 effect. Targeted knockdown or overexpression of pathways identified to be downstream of ORMDL3 will demonstrate their contribution to the function of CD4 cells. Finally, we are using single base editing to edit SNPs linked to ORMDL3 to determine which SNPs functionally regulate levels of ORMDL3, Th2 cytokines, and downstream pathways of ORMDL3.


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 = $558,606 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	10	5/29/2024	NON-COMPETING CONTINUATION	$55,862
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	10	2/28/2024	NON-COMPETING CONTINUATION	$502,744
														Subtotal = $558,606

Issue Date FY: 2023 ( Subtotal = $561,375 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	9	2/6/2023	NON-COMPETING CONTINUATION	$561,375
														Subtotal = $561,375

Issue Date FY: 2022 ( Subtotal = $564,143 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	8	3/1/2022	NON-COMPETING CONTINUATION	$564,143
														Subtotal = $564,143

Issue Date FY: 2021 ( Subtotal = $566,385 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	7	2/9/2021	NON-COMPETING CONTINUATION	$566,385
														Subtotal = $566,385

Issue Date FY: 2020 ( Subtotal = $582,499 )
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	6	3/20/2020	COMPETING CONTINUATION	$501,957
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	001	6	8/25/2020	COMPETING CONTINUATION	$80,542
														Subtotal = $582,499

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2017	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	5	9/10/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $387,500 )
2017	2017	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	5	3/30/2017	NON-COMPETING CONTINUATION	$387,500
														Subtotal = $387,500

Issue Date FY: 2016 ( Subtotal = $387,500 )
2016	2016	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	4	4/15/2016	EXTENSION WITH OR WITHOUT FUNDS	$387,500
														Subtotal = $387,500

Issue Date FY: 2015 ( Subtotal = $387,500 )
2015	2015	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	3	4/16/2015	NON-COMPETING CONTINUATION	$387,500
														Subtotal = $387,500

Issue Date FY: 2014 ( Subtotal = $387,500 )
2014	2014	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	2	4/9/2014	NON-COMPETING CONTINUATION	$387,500
														Subtotal = $387,500

Issue Date FY: 2013 ( Subtotal = $364,250 )
2013	2013	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Allergy and Infectious Diseases Research	000	1	5/14/2013	NEW	$364,250
														Subtotal = $364,250

Grand Total All Awards = $4,747,258

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Chromosome 17q21, allergic inflammation, and remodeling

Award Number: R01AI107779

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: 05/15/2013

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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