Development of therapeutics to prevent spontaneous preterm birth

自发性早产（sPTB）影响10 - 15%的妊娠，并导致大多数（约80%）新生儿 死亡率和发病率。预防sPTB的合理治疗策略是阻断早产。我们提出 这可以通过利用类固醇激素孕酮（P4）的促孕作用来实现。 临床研究表明，预防性P4治疗可降低早产的发生率， 靶向P4预防早产的治疗潜力。然而，目前的治疗方法在以下方面有效： 只有一小部分怀孕。我们的目标是改善预防性P4治疗， 在所有的怀孕。为了做到这一点，拟议的研究建立在4个数据驱动的概念：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： 通过子宫肌层细胞中的抗炎作用抑制子宫肌层炎症; 3）分娩由 功能性P4撤退，由此子宫肌层细胞变得对P4抗炎活性不敏感，和4） 功能性P4撤退是由A型P4受体（PR）亚型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孕酮 受体（PR）调节剂（SPRM），增强抗炎（因此促孕）作用 并同时抑制pSer344/345-PRA的产生（从而抑制功能性P4/PR撤回） 可以预防sPTB我们的目标是确定SPRM化合物与这些属性。为实现这些目标将 解决2个具体目标：1）使用已知的SPRM结构来开发发挥PR介导的 抗炎活性和抑制子宫肌层细胞中pSer344/345-PRA的产生;和2）鉴定SPRM 抑制小鼠中炎症诱导的分娩的化合物（来自目的1）。我们的初步数据 支持我们的中心假设的核心原则，我们已经确定了8个SPRM化合物，发挥PR- 在子宫肌层细胞中介导的抗炎活性，以及一种降低子宫内膜炎发生率的化合物， 炎症诱导的小鼠分娩。我们的分析计划侧重于SPRM的翻译潜力 使用涉及人子宫肌层细胞的严格SPRM筛选方案和 炎症诱导分娩的小鼠模型。我们的目标是开发10 - 15个先导化合物。项目 具有重要的转化潜力，因为它是开发安全， 廉价的基于SPRM的预防性治疗，以降低所有女性的sPTB发病率。

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.