权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Development of therapeutics to prevent spontaneous preterm birth

开发预防自发性早产的疗法

基本信息

批准号：
10549723
负责人：
Sam Antonio MESIANO
金额：
$ 33.53万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10549723
关键词：
Address Affect Anti-Inflammatory Agents Antiinflammatory Effect Birth Cells Cervical Clinical Clinical Research Cyclic AMP-Dependent Protein Kinases Data Decidual Cell Development Disease Drug Design Environment Event Fetal Development Funding Opportunities Generations Goals Human Incidence Induced Labor Inflammation Inflammatory Lead Ligands Mediating Modeling Molecular Biology Molecular Target Mus Myometrial Neonatal Intensive Care Units Neonatal Mortality Nuclear Pathologic Pathway interactions Phase Phosphorylation Phosphotransferases Pregnancy Premature Birth Premature Labor Prevention Production Progesterone Progesterone Receptors Property Prophylactic treatment Prostaglandins Protein Isoforms Publishing Refractory Regimen Repression Research Secondary to Serine Stimulus Structure Testing Therapeutic Time Tissues Uterus Validation Withdrawal Woman cytokine desensitization improved mouse model myometrium neonatal morbidity predictive modeling prevent prophylactic receptor response screening socioeconomics steroid hormone therapeutic development transcription factor translational potential

项目摘要

Spontaneous preterm birth (sPTB) affects 10-15% of pregnancies and causes the majority (~80%) of neonatal mortality and morbidity. A logical therapeutic strategy to prevent sPTB is to block preterm labor. We propose that this may be achieved by exploiting the pro-gestational actions of the steroid hormone progesterone (P4). Clinical studies showing that prophylactic P4 therapy decreases the incidence of preterm birth, demonstrate the therapeutic potential of targeting P4 to prevent preterm birth. Current therapies, however, are effective in only a small subset of pregnancies. Our goal is to improve prophylactic P4 therapy so that it prevents preterm birth in all pregnancies. To do this the proposed research builds on 4 data-driven concepts: 1) that labor is secondary to tissue-level inflammation within the myometrium; 2) that P4 promotes myometrial quiescence by repressing myometrial inflammation via anti-inflammatory effects in myometrial cells; 3) labor is triggered by functional P4 withdrawal whereby myometrial cells become refractory to P4 anti-inflammatory activity, and 4) functional P4 withdrawal is induced by phosphorylation of the type-A P4 receptor (PR) isoform, PR-A, at serine-344 and -345 (pSer344/345-PRA). In this context, our core hypothesis is that selective progesterone receptor (PR) modulators (SPRMs) that enhance the anti-inflammatory (and therefore pro-gestational) actions of PR and simultaneously inhibit the generation of pSer344/345-PRA (and therefore functional P4/PR withdrawal) will prevent sPTB. Our objective is to identify SPRM compounds with these properties. This will be achieved by addressing 2 Specific Aims: 1) use known SPRM structures to develop compounds that exert PR-mediated anti-inflammatory activity and inhibit pSer344/345-PRA generation in myometrial cells; and 2) identify SPRM compounds (from Aim 1) that inhibit inflammation-induced parturition in the mouse. Our preliminary data support the core tenets of our central hypothesis and we have identified 8 SPRM compounds that exert PR- mediated anti-inflammatory activity in myometrial cells and one compound that decreases the incidence of inflammation-induced parturition in the mouse. Our analysis plan focuses on translational potential of SPRMs for the prevention of sPTB using a stringent SPRM screening regimen involving human myometrial cells and a mouse model for inflammation-induced parturition. Our goal is to develop 10-15 lead compounds. The project has significant translational potential because it is the foundational study for the development of safe, inexpensive SPRM-based prophylactic therapies to reduce the incidence of sPTB in all women.

自发性早产（sPTB）影响10-15%的妊娠，并导致大多数（~80%）新生儿