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%) 新生儿死亡率和发病率。预防 sPTB 的合理治疗策略是阻止早产。我们建议这可以通过利用类固醇激素黄体酮 (P4) 的促妊娠作用来实现。临床研究表明预防性 P4 治疗可降低早产发生率靶向 P4 预防早产的治疗潜力。然而，目前的疗法在以下方面有效：仅怀孕的一小部分。我们的目标是改进预防性 P4 治疗，以预防早产所有妊娠中的分娩。为此，拟议的研究建立在 4 个数据驱动的概念之上：1）劳动力是继发于子宫肌层内的组织水平炎症； 2）P4通过以下方式促进子宫肌层静止：通过子宫肌细胞的抗炎作用抑制子宫肌层炎症； 3) 分娩的触发因素是功能性 P4 撤退，使子宫肌细胞对 P4 抗炎活性产生耐药性，以及 4) 功能性 P4 戒断是由 A 型 P4 受体 (PR) 同种型 PR-A 的磷酸化诱导的，丝氨酸-344 和-345 (pSer344/345-PRA)。在这种情况下，我们的核心假设是选择性黄体酮增强抗炎（从而促妊娠）作用的受体（PR）调节剂（SPRM） PR 并同时抑制 pSer344/345-PRA 的生成（从而抑制功能性 P4/PR 撤退）将预防 SPTB。我们的目标是识别具有这些特性的 SPRM 化合物。这将通过以下方式实现解决 2 个具体目标：1) 使用已知的 SPRM 结构来开发发挥 PR 介导作用的化合物抗炎活性并抑制子宫肌细胞中 pSer344/345-PRA 的生成； 2) 识别 SPRM 抑制小鼠炎症诱导分娩的化合物（来自目标 1）。我们的初步数据支持我们中心假设的核心原则，我们已经确定了 8 种 SPRM 化合物，它们发挥 PR- 介导子宫肌层细胞的抗炎活性，以及一种可降低子宫肌瘤发生率的化合物炎症诱导的小鼠分娩。我们的分析计划侧重于 SPRM 的转化潜力使用严格的 SPRM 筛查方案来预防 sPTB，该方案涉及人类子宫肌细胞和炎症诱导分娩的小鼠模型。我们的目标是开发 10-15 种先导化合物。项目具有重大的转化潜力，因为它是开发安全、廉价的基于 SPRM 的预防性疗法可降低所有女性的 sPTB 发病率。