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Anti-inflammatory drug target to reduce adverse pregnancy outcomes.

Award Number: R01HD098389
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2019
PERIOD OF PERFORMANCE END DATE: 03/31/2024

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Anti-inflammatory drug target to reduce adverse pregnancy outcomes. - Abstract Intrauterine infection/inflammation (IUI) is a major contributor to preterm labor and fetal inflammation leading to injury responses in fetal organs such as the brain, lung and the GI tract. However, the mechanisms and precise therapeutic approaches remain elusive largely because of lack of relevant animal models. We have developed a powerful new model of intrauterine infection in preterm Rhesus macaques: Intraamniotic (IA) injection of live E. coli followed 24h later with antibiotics. This model results in persistent IUI. Importantly, the maternal and fetal inflammation persists despite clearance of E. coli bacteremia, resulting in preterm labor (PTL), fetal immune aberrations and fetal neuroinflammation. We now propose validating IL1 as a drug target for IUI induced prematurity and fetal inflammation. This grant is based on our data that Anakinra (IL1 receptor antagonist used clinically for rheumatoid arthritis) significantly decreased neutrophilic infiltration at the maternal-fetal interface and amniotic fluid IL6, PGE2 in a different but widely used model of IA LPS. Furthermore, Anakinra reversed the LPS-induced “inflammatory Treg” in the fetal spleen. We propose to test the hypothesis that Anakinra will reduce the residual maternal and fetal inflammation in infectious models that closely simulate IUI in pregnant women with two Aims. In Aim 1, we will ask if anti IL1 directed anti- inflammatory therapy will decrease intrauterine infection induced inflammation and preterm labor. We will use state-of-the-art single-cell transcriptomic approach to unravel cellular and molecular mechanisms of inflammation at the maternal-fetal interface, define labor associated pathways of IUI that are responsive to IL1 inhibition. Using multi-parameter flow cytometry, we will identify mechanisms of neutrophil recruitment and activation in the chorio-decidua. In Aim 2, We will identify mucosal and systemic fetal immune perturbations resulting from transient bacteremia and sterile fetal inflammation. We will determine if Anakinra can reduce fetal systemic inflammation and neuroinflammation resulting from IUI. These studies will develop the critical knowledge base for future studies aimed at repurposing of Anakinra as a novel anti-inflammatory therapy for human IUI. A collaborative multi-disciplinary team will use high-resolution immunology, genomics/proteomics, neuro-science, and translational approaches in modeling IUI and fetal inflammation in an animal model that closely mimics the human pathology.


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: 2023 ( Subtotal = $693,743 )
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Child Health and Human Development Extramural Research	000	5	2/22/2023	NON-COMPETING CONTINUATION	$693,743
														Subtotal = $693,743

Issue Date FY: 2022 ( Subtotal = $679,641 )
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Child Health and Human Development Extramural Research	000	4	5/5/2022	NON-COMPETING CONTINUATION	$679,641
														Subtotal = $679,641

Issue Date FY: 2021 ( Subtotal = $703,958 )
2021	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Child Health and Human Development Extramural Research	000	3	3/28/2021	NON-COMPETING CONTINUATION	$703,958
														Subtotal = $703,958

Issue Date FY: 2020 ( Subtotal = $985,675 )
2020	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Microbiology and Infectious Diseases Research	001	2	9/14/2020	SUPPLEMENT FOR EXPANSION	$267,351
2020	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Child Health and Human Development Extramural Research	000	2	4/17/2020	NON-COMPETING CONTINUATION	$718,324
														Subtotal = $985,675

Issue Date FY: 2019 ( Subtotal = $721,511 )
2019	2019	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Child Health and Human Development Extramural Research	001	1	6/7/2019	NEW	$0
2019	2019	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Child Health and Human Development Extramural Research	000	1	5/30/2019	NEW	$721,511
														Subtotal = $721,511

Grand Total All Awards = $3,784,528

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Anti-inflammatory drug target to reduce adverse pregnancy outcomes.

Award Number: R01HD098389

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2019

PERIOD OF PERFORMANCE END DATE: 03/31/2024

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