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Therapeutic targeting of FKBP51 for the prevention of stress-induced preterm birth

FKBP51 预防应激性早产的治疗靶点

基本信息

批准号：
10758367
负责人：
DAVID R FRIEND
金额：
$ 38.5万
依托单位：
DARE BIOSCIENCE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10758367
关键词：
AKR1C1 Affect Animals Binding Biological Biological Sciences Birth Birth Rate Birth Weight Black race Brain Cell Culture Techniques Cell Line Cell Nucleus Cells Cerebral Palsy Clinical Collaborations Combined Modality Therapy Complex Corticosterone Cytoplasm Data Decidual Cell Development Discipline of obstetrics Disease Dose Economic Burden Endometrium Enzymes FDA approved FK506 binding protein 5 Face Family Fetus Florida Gastrointestinal tract structure Goals Health Hearing High Risk Woman Human Hydroxysteroid Dehydrogenases In Vitro Induced Labor Infant Mortality Injectable Intraperitoneal Injections Knockout Mice Laboratories Length Length of Stay Ligands Link Litter Size Lung Marketing Maternal-Fetal Exchange Measures Mediating Messenger RNA Metabolism Modeling Molecular Mothers Mus Necrotizing Enterocolitis Newborn Infant Nuclear Pathway interactions Phase Phase I Clinical Trials Placebos Pregnancy Pregnancy Maintenance Pregnant Women Premature Birth Premature Infant Prevention Prevention approach Prevention strategy Progesterone Progesterone Receptors Progestins Prophylactic treatment Prostaglandins Proteins RU-5020 Recommendation Reporting Resistance Risk Risk Factors Role Route Safety Schools Serum Small Business Technology Transfer Research Steroids Stress Survivors Synthetic Progestogens Therapeutic Treatment Efficacy United States Universities Uterus Vagina Vision Wild Type Mouse Withdrawal Woman Work biological adaptation to stress clinically relevant deafness efficacy testing improved improved outcome in vivo infant outcome inflammatory marker inhibitor maternal stress maternal weight mouse model new therapeutic target novel novel strategies novel therapeutic intervention pharmacologic pregnant premature prevent primary endpoint pup research and development respiratory distress syndrome side effect skills social standard of care therapeutic target treatment effect treatment group treatment strategy validation studies

项目摘要

In the United States, one in ten babies is born prematurely. The earlier in pregnancy a baby is born, the more likely they will have an extended hospital stay, as well as serious health complications such as respiratory distress syndrome, necrotizing enterocolitis, deafness, vision problems and cerebral palsy. Maternal stress is a well-established risk factor for preterm birth, and recent studies using a mouse model of maternal stress highlight the role of a stress response protein, FKBP51, in promoting preterm birth. Prior work demonstrates that stress boosts FKBP51 expression. Consequently, FKBP51 binds to progesterone receptors in decidual cells at the maternal-fetal interface, reducing progesterone receptor activity in the nucleus, resulting in the functional withdrawal of progesterone that triggers labor and birth in humans. Importantly, this novel molecular pathway can be blocked by 15-deoxy-Δ12,14-prostaglandin J2 (15dPGJ2), restoring the activity of progesterone receptors in vitro and in vivo. Thus, therapeutic targeting of FKBP51 has great potential as a safe and effective strategy to prevent preterm birth. Because there exist no pharmacological strategies for the prevention of preterm birth, Daré Bioscience, in collaboration with the University of South Florida, aims to rigorously demonstrate the feasibility of targeting FKBP51 to improve obstetric treatment options for women. Work in Aim 1 is focused on validating FKBP51 as a novel drug target using clinically-relevant human decidual cell culture models, selecting a therapeutic strategy that combines 15dPGJ2 with delivery of a progestin, and evaluating the downstream biological effects of treatment. The focus of Aim 2 is to demonstrate the in vivo safety and efficacy of 15dPGJ2 plus progestin combination therapy for pregnancy maintenance in a previously validated maternal stress induced mouse model of preterm birth. The goal is to demonstrate a statistically significant increase in gestational length by treatment(s) in stressed animals vs. untreated stressed controls. This project has significant translational and commercial potential because it will provide the necessary proof-of-concept data to advance a treatment strategy to Phase II IND-enabling studies.

在美国，十分之一的婴儿早产。婴儿在怀孕越早出生，就会有更多的