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Development of allergy in offspring is enhanced by maternal eicosanoids and lung microbiota composition dysbiosis.

Award Number: R01AI180448
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: 11/08/2023
PERIOD OF PERFORMANCE END DATE: 10/31/2028

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Development of allergy in offspring is enhanced by maternal eicosanoids and lung microbiota composition dysbiosis. - The greatest risk factor for development of allergies and asthma in offspring is a parental history of allergic disease. Maternal transmission of reactivity that is not specific for allergen has been demonstrated in patients and animal models. We demonstrated that there are increased numbers of subsets of dendritic cells (DCs) in the fetal liver and offspring of allergic mothers. In preliminary animal studies, intratracheal transfer of lung dendritic cells (DCs) or lung microbiota from neonates of allergic mothers transfers allergen responsiveness to recipient neonates of non-allergic mothers. The mechanisms for regulation of offspring DCs and allergy by factors from allergic mothers are not well defined. We propose the novel concept that increases in the eicosanoids dihydroxyeicosatrienoic acids (DHETs) in allergic mothers are transported to the offspring, where the DHETs regulate development of lung microbiota dysbiosis and offspring responsiveness to allergens. In our preliminary lipidomics analyses, DHETs but not other eicosanoids were elevated in plasma of allergic mothers and in fetuses, suggesting a potential function of this eicosanoid in development of allergy. In preliminary studies, the development of bone marrow-derived DCs (BMDCs) was increased in vitro by DHET; also human cord blood DHET levels correlated with infant wheeze. However, regulatory functions of maternal DHETs in the development of offspring DCs and allergy are not known. Unknown are mechanisms for 1) maternal increases in DHET, 2) DHET regulation of DC development in offspring, and 3) the reciprocity between lung microbiome and host eicosanoid metabolism. Our long-term goal is to identify mechanisms for maternal DHET regulation of offspring development of allergic responses. As a step towards our goal, our central HYPOTHESIS is that increases in DHET levels in allergic mothers regulate the development of offspring numbers of pro-allergic DC subsets, lung microbiota dysbiosis, and responses to allergen early in life. We will test our central hypothesis with the following aims: Aim 1. Test the hypothesis that, a mechanism for increasing responsiveness to allergen in offspring of allergic mothers is increased maternal lung DHETs that are transferred in utero to the fetus and in milk to neonates. Aim 2. Test the hypothesis that increased levels of DHETs in allergic mothers is a mechanism for increased hematopoiesis of fetal liver and pup bone marrow DC subsets and DC function in allergic responses. We will also determine whether human cord blood plasma DHETs associate with infant atopy and DC numbers. Aim 3. Test the hypothesis that increased DHETs of allergic mothers is a mechanism for induction of maternal and neonate lung microbiome dysbiosis, thereby increasing the abundance of lung bacteria that metabolize DHETs that then sustain increased offspring DC responsiveness to allergen. In human infants, we will determine whether cord blood eicosanoid profiles associate with infant airway bacterial microbiota, lung function, and wheeze. Completion of these studies will have a significant impact on understanding mechanisms of maternal lipid regulation of offspring DCs during development of allergies and design of future clinical studies.


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 = $785,490 )
2026	2026	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Allergy and Infectious Diseases Research	000	3	12/8/2025	NON-COMPETING CONTINUATION	$785,490
														Subtotal = $785,490

Issue Date FY: 2025 ( Subtotal = $761,923 )
2025	2025	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Allergy and Infectious Diseases Research	000	2	11/1/2024	NON-COMPETING CONTINUATION	$761,923
														Subtotal = $761,923

Issue Date FY: 2024 ( Subtotal = $805,935 )
2024	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Allergy and Infectious Diseases Research	001	1	9/3/2024	NEW	$80,119
2024	2024	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Allergy and Infectious Diseases Research	000	1	11/8/2023	NEW	$725,816
														Subtotal = $805,935

Grand Total All Awards = $2,353,348

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Development of allergy in offspring is enhanced by maternal eicosanoids and lung microbiota composition dysbiosis.

Award Number: R01AI180448

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: 11/08/2023

PERIOD OF PERFORMANCE END DATE: 10/31/2028

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