Development of therapeutics to prevent spontaneous preterm birth

开发预防自发性早产的疗法

• 批准号: 10320868
• 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
• 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/10320868
• 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; Foundations; 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; Problem Solving; Production; Progesterone; Progesterone Receptors; Property; Prophylactic treatment; Prostaglandins; Protein Isoforms; Publishing; Refractory; Regimen; Research; Secondary to; Serine; Stimulus; Structure; Testing; Therapeutic; Time; Tissues; Uterus; Validation; Withdrawal; Woman; base; contextual factors; cytokine; desensitization; improved; mouse model; myometrium; neonatal morbidity; predictive modeling; prevent; prophylactic; receptor; response; screening; socioeconomics; steroid hormone; therapeutic development; transcription factor; translational potential

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.

自发早产（SPTB）影响10-15％的怀孕，并导致大多数（〜80％）的新生儿 死亡率和发病率。防止SPTB的逻辑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孕激素的促孕作用（P4）来实现。 临床研究表明，预防性P4治疗降低了早产的发生率，证明 靶向P4防止早产的治疗潜力。但是，当前的疗法有效 只有一小部分怀孕。我们的目标是改善预防性P4疗法，以防止早产 在所有怀孕中出生。为此，拟议的研究以4个数据驱动概念为基础：1）劳动是 继发于肌层内的组织水平炎症； 2）P4通过 通过肌层细胞中的抗炎作用抑制肌层炎症； 3）劳动是由 功能性P4提取，肌层细胞对P4抗炎活性产生难治性，而4） 功能性P4戒断是由A型P4受体（PR）同工型（PR-A）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（SPRMS）增强了抗炎（以及促胎）作用 PR并同时抑制PSER344/345-PRA的产生（因此功能性P4/PR提取） 将防止SPTB。我们的目标是识别具有这些特性的SPRM化合物。这将通过 解决2个具体目的：1）使用已知的SPRM结构开发出发动PR介导的化合物 抗炎活性并抑制肌层细胞中PSER344/345-PRA的产生； 2）识别SPRM 化合物（来自AIM 1），抑制小鼠炎症诱导的分娩。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种具有PR-的SPRM化合物 肌层细胞中介导的抗炎活性和一种化合物，可降低 小鼠炎症引起的分娩。我们的分析计划着重于Sprms的翻译潜力 为了使用涉及人肌层细胞和A的严格的SPRM筛选方案预防SPTB 炎症引起的分娩的小鼠模型。我们的目标是开发10-15种铅化合物。项目 具有巨大的翻译潜力，因为它是安全开发的基础研究 廉价的基于SPRM的预防疗法可降低所有女性SPTB的发生率。