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Nanomedicine-based approach for characterizing the epigenome in prevention of inflammation-induced preterm birth.

Award Number: R01HD108905
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: 12/21/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Nanomedicine-based approach for characterizing the epigenome in prevention of inflammation-induced preterm birth. - PROJECT SUMMARY Preterm birth (PTB), or birth before 37 weeks of gestation, was the second leading cause of infant death in the US in 2017. Each year, more than $26 billion is spent on treatment and care of babies born prematurely, not accounting for the lifelong impact of developmental and cognitive impairments. Earlier this year, the FDA issued a recommendation that the synthetic progestin 17-hydroxyprogesterone caproate (OHPC, Makena®), the only approved product for PTB prevention, be withdrawn from the market due to lack of clinical benefit in a required post-market study. New and innovative therapeutic options for preventing PTB are desperately needed, but the etiology of PTB is complex and the potential for tissue sampling and clinical trials during pregnancy is limited. We recently developed an adapted mouse model of inflammation-induced PTB and a unique nanomedicine-based approach for more efficient vaginal delivery of therapeutics to the reproductive tract. Together, these new tools led to the first demonstration of therapeutic prevention of early intrauterine inflammation-induced PTB that led to full term delivery of litters with high percentages of pup viability and neurotypical motor development. The therapeutics delivered via the nanoformulation were histone deacetylase inhibitors (HDACi) dosed with or without the need for additional exogenous progesterone (P4). HDACi prevent deacetylation of histones, leading to more transcriptionally active chromatin, and thus, changes in gene expression. We also observed that the P4/HDACi combination inhibited human myometrial cell contractility and led to an increase in the ratio of P4 receptor (PR) isoform B (PR-B) compared to P4 receptor isoform A (PR-A), which is thought to maintain uterine quiescence and cervical competence. This supports the idea that HDACi- induced hyperacetylation creates a more favorable chromatin structure for ligand-bound PR to change the gene expression profile in a manner that prevents PTB. The overarching goals of this proposal are to determine the role of PR-B in the prevention of inflammation-induced PTB, to map epigenetic changes that are specific to therapeutic treatment, and to evaluate whether the epigenetic changes are sufficient to reset the uterine environment for normal fetal development. If these preclinical studies are successful, we will generate fundamental mechanistic knowledge of epigenetic regulation in PTB, as well as identify new cellular pathways that may be important targets for PTB prevention.


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 = $608,481 )
2026	2026	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Child Health and Human Development Extramural Research	000	4	12/9/2025	NON-COMPETING CONTINUATION	$547,632
2026	2026	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Child Health and Human Development Extramural Research	001	4	3/27/2026	NON-COMPETING CONTINUATION	$60,849
														Subtotal = $608,481

Issue Date FY: 2025 ( Subtotal = $608,481 )
2025	2025	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Child Health and Human Development Extramural Research	000	3	11/22/2024	NON-COMPETING CONTINUATION	$547,632
2025	2025	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Child Health and Human Development Extramural Research	001	3	4/14/2025	NON-COMPETING CONTINUATION	$60,849
														Subtotal = $608,481

Issue Date FY: 2024 ( Subtotal = $602,396 )
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Child Health and Human Development Extramural Research	000	2	11/14/2023	NON-COMPETING CONTINUATION	$547,632
2024	2024	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Child Health and Human Development Extramural Research	001	2	5/6/2024	NON-COMPETING CONTINUATION	$54,764
														Subtotal = $602,396

Issue Date FY: 2023 ( Subtotal = $624,419 )
2023	2023	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Child Health and Human Development Extramural Research	000	1	12/21/2022	NEW	$624,419
														Subtotal = $624,419

Grand Total All Awards = $2,443,777

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Nanomedicine-based approach for characterizing the epigenome in prevention of inflammation-induced preterm birth.

Award Number: R01HD108905

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: 12/21/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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