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Maternal programming of the stem cell-basophil axis for asthma

Award Number: R01AI143837
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: 07/20/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Maternal programming of the stem cell-basophil axis for asthma - Project Summary/Abstract A growing number of epidemiological studies link childhood asthma with maternal environmental exposures with the strongest evidence provided for diesel exhaust and cigarette smoke. How maternal exposures lead to asthma in offspring is unknown. To address this, we developed a mouse model of asthma susceptibility in pups by exposing their mothers to diesel exhaust particles (DEP). Our data suggests that in this DEP-driven model, asthma-predisposing information is transmitted in part by a subset of offspring long-term hematopoietic stem cells (LT-HSCs), in the form of a stem cell memory. This subset distinguishes itself by expression of the IL3 receptor and is programmed for enhanced generation of basophils by the synergistic action of DEP-induced IL1b and IL3. One key mechanism of the synergism between IL1b and IL3 is the ability of IL1b to increase stem cell sensitivity to IL3 which is in part due to IL1b-mediated upregulation of IL3R b chain. In addition to expanding the basophil lineage, IL3 and IL1b are likely to enhance its capacity to promote asthma. Previous studies show that IL1b potentiates basophil histamine release and IL3 potently stimulates their IL4 production, sowing the seed for type-2 immune response. Consistent with this, in DEP offspring, basophils overexpress IL4. The IL3/IL1b-primed, expanded, IL4-overexpressing basophil population becomes a key driver of the type- 2 immune response and asthma upon allergen challenge. Basophil depletion in DEP pups prevents generation of allergen-specific IgE and development of asthma. This is in contrast with data obtained in plain allergen- based models in which basophils are redundant for production of IgE and asthma. Our overarching hypothesis is that maternal exposure to DEP induces asthma susceptibility in offspring through IL1b and IL3 driven programming of the hematopoietic stem cell-basophil axis. In Aim 1, by performing stem cell transplantation experiments, we will establish links between DEP IL3R+ LT-HSCs, increased basopoiesis and predisposition to asthma. We will define molecular basis of DEP IL3R+ LT-HSC programming by analyzing their transcriptomes (RNA-seq) and chromatin remodeling at gene regulatory sites (ATAC-seq). In Aim 2 we will study importance of IL1b and IL3 in programming of the HSC-basophil axis for asthma induction. In our model, IL1b and IL3 are increased in offspring and maternal tissues, including maternal serum. We propose that maternal IL1b and IL3 are important at early stages of embryonic hematopoiesis, when HSCs undergo their initial divisions and embryonic sources of IL1b and IL3 are scarce. Offspring-derived IL1b and IL3 complete the HSC programming process, sustain basopoiesis at a high level, and contribute to basophil activation after maternal cytokines fade away. To define how maternal IL1b and IL3 are transferred to embryos, study their roles and roles of offspring- encoded IL1b and IL3, we will perform serum transfers, injections with radiolabeled cytokines, and combine IL1b or IL3 KO strategies with embryo transfers. In Aim 3 we will use human blood samples to study IL1b and IL3 guided basophil development in childhood asthma.


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 = -$5,603 )
2026	2024	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Allergy and Infectious Diseases Research	000	4	12/18/2025	NON-COMPETING CONTINUATION	-$5,603
														Subtotal = -$5,603

Issue Date FY: 2024 ( Subtotal = $610,821 )
2024	2024	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Allergy and Infectious Diseases Research	000	4	6/5/2024	NON-COMPETING CONTINUATION	$610,821
														Subtotal = $610,821

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Allergy and Infectious Diseases Research	000	3	7/25/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $689,600 )
2022	2022	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Allergy and Infectious Diseases Research	000	3	6/15/2022	NON-COMPETING CONTINUATION	$689,600
														Subtotal = $689,600

Issue Date FY: 2021 ( Subtotal = $631,806 )
2021	2021	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Allergy and Infectious Diseases Research	000	2	6/30/2021	NON-COMPETING CONTINUATION	$631,806
														Subtotal = $631,806

Issue Date FY: 2020 ( Subtotal = $626,821 )
2020	2020	NATIONAL JEWISH HEALTH	1400 JACKSON ST	DENVER	CO	80206	DENVER	USA	Allergy and Infectious Diseases Research	000	1	7/20/2020	NEW	$626,821
														Subtotal = $626,821

Grand Total All Awards = $2,553,445

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Maternal programming of the stem cell-basophil axis for asthma

Award Number: R01AI143837

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: 07/20/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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