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Regulation of Gene Expression in the anaphylactic Pathway

Award Number: R01AI135194
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: 05/15/2018
PERIOD OF PERFORMANCE END DATE: 04/30/2024

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Regulation of Gene Expression in the anaphylactic Pathway - Project Summary This proposal investigates the regulation of three selected genes that encode proteins that are critical for anaphylaxis that is mediated by IgE and mast cells (MCs). MCs release inflammatory mediators, including histamine, in response to antigen crosslinking of the IgE/FceRI complex; these mediators play a major role in causing IgE-mediated anaphylactic shock. Although much is known about the proteins that are involved in MC activation, signal transduction and mediator synthesis, little is known about how the genes that encode these critical proteins are regulated. We and others have demonstrated that the transcription factors (TFs) GATA2 and MITF are essential for MC development and maintenance. However, it remains largely unexplored how these and additional TFs interact with their target enhancers to regulate the expression of target genes that are important in mediating histamine synthesis, MC activation, and IgE-mediated disorders, including anaphylaxis and food allergy. Our long-term goal is to enhance fundamental understanding of the regulation of MC genes that influence food allergy susceptibility and severity. Our central hypothesis is that GATA2 and MITF detect MC activation signals, induce chromatin accessibility in genes essential in the anaphylactic pathway, and recruit other TFs to form a promoter/enhancer transcription complex that activates Hdc gene transcription in a switch-like manner (Hdc encodes histidine decarboxylase, the rate limiting enzyme in histamine synthesis). This central hypothesis is strongly supported by our preliminary data and will be tested in 3 aims that are conceptually innovative and make use of innovative technology. In Aim 1, we will determine how the TFs GATA2, MITF, MECOM and their target promoters and enhancers regulate the expression of Hdc and two other genes that are essential in the IgE/MC-mediated anaphylactic pathway: Fcer1a, which encodes the IgE- binding chain of the high affinity IgE receptor, and Pi3p85, which encodes the P85 regulatory chain of PI3K kinase, a signaling molecule required for MC degranulation. In Aim2, we will identify the enhancers and their associated TFs that regulate these genes in humans. In Aim3, we will analyze the function of Hdc enhancers in IgE/MC-mediated anaphylaxis. Upon completion of the planned studies, we will understand substantially more about the mechanisms through which MCs mediate anaphylaxis in both mouse and human. The acquired knowledge should promote understanding of gene regulation in general and the regulation of genes that influence food allergy susceptibility and severity in particular. As a result, these studies should promote the development of effective interventions to prevent and treat food allergy and other IgE-mediated allergic disorders.


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: 2025 ( Subtotal = $0 )
2025	2022	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Allergy and Infectious Diseases Research	000	5	11/22/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $604,952 )
2022	2022	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Allergy and Infectious Diseases Research	000	5	4/15/2022	NON-COMPETING CONTINUATION	$604,952
														Subtotal = $604,952

Issue Date FY: 2021 ( Subtotal = $604,952 )
2021	2021	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Allergy and Infectious Diseases Research	000	4	4/28/2021	NON-COMPETING CONTINUATION	$604,952
														Subtotal = $604,952

Issue Date FY: 2020 ( Subtotal = $604,952 )
2020	2020	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Allergy and Infectious Diseases Research	001	3	4/3/2020	NON-COMPETING CONTINUATION	$604,952
2020	2019	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Allergy and Infectious Diseases Research	000	2	3/24/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $604,952

Issue Date FY: 2019 ( Subtotal = $680,100 )
2019	2019	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Allergy and Infectious Diseases Research	000	2	3/22/2019	NON-COMPETING CONTINUATION	$680,100
														Subtotal = $680,100

Issue Date FY: 2018 ( Subtotal = $644,534 )
2018	2018	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Allergy and Infectious Diseases Research	000	1	5/15/2018	NEW	$644,534
														Subtotal = $644,534

Grand Total All Awards = $3,139,490

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Regulation of Gene Expression in the anaphylactic Pathway

Award Number: R01AI135194

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: 05/15/2018

PERIOD OF PERFORMANCE END DATE: 04/30/2024

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