Discovery of Novel Therapeutics for Inflammation Induced Preterm Birth

发现治疗炎症引起的早产的新疗法

• 批准号: 10429552
• 负责人: Shajila Siricilla
• 金额: $ 10.77万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10429552
• 关键词: 37 weeks gestation; Academic Medical Centers; Adverse effects; Advisory Committees; Affect; Agonist; Amniotic Fluid; Antibiotics; Bacteria; Biological Assay; Biology; Birth; Chemicals; Clinical; Communicable Diseases; Continuing Education; Custom; Decidua; Development; Discipline of obstetrics; Dose; Drug Combinations; Drug Targeting; Educational workshop; Ensure; Escherichia coli; Exposure to; Fetal Tissues; Fetus; Future; Gene Targeting; Genes; Genome; Goals; Grant; Hematogenous; Human; IL6 gene; In Vitro; Indomethacin; Infant Mortality; Infection; Inflammation; Inflammatory; Innate Immune System; Intervention; Lead; Libraries; Measurement; Measures; Mediating; Mediator of activation protein; Membrane; Mentors; Mentorship; Molecular; Molecular Bank; Monitor; Morbidity - disease rate; Mus; Neonatal; Neonatology; Non-Steroidal Anti-Inflammatory Agents; Pathologic; Pathway interactions; Pattern; Pharmacology; Phase; Phenotype; Physiology; Pregnancy; Premature Birth; Premature Labor; Primates; Reaction; Records; Regulation; Reproducibility; Reproductive Sciences; Research; Research Personnel; Resources; Route; Series; Signal Pathway; Streptococcus Group B; Structure; Testing; Therapeutic; Therapeutic Agents; Tissue Model; Tissues; Training; Treatment Efficacy; Ureaplasma urealyticum; Vagina; Work; Writing; base; career development; cytokine; cytotoxicity; drug discovery; druggable target; early pregnancy; experience; fetal; fetal inflammatory response syndrome; global health; high throughput screening; in utero; in vivo; infant morbidity/mortality; infection management; inhibitor; interest; intraamniotic infection; intrapartum; intrauterine infection; intrauterine inflammation; microbial; microorganism; mouse model; multidisciplinary; neonatal outcome; novel; novel strategies; novel therapeutics; pathogen; prenatal exposure; prevent; programs; responsible research conduct; screening; side effect; small molecule; small molecule inhibitor; small molecule libraries; success; symposium; therapeutic effectiveness; therapeutically effective; transcriptome; transcriptomics

PROJECT SUMMARY In this K99/R00 Pathway to Independence application, the candidate proposes a structured, rigorous and detailed training plan to build expertise in ex vivo gestational tissue modeling and preterm birth physiology along with continued education in the latest approaches for drug discovery. This training plan will be supported through hands-on-training, coursework, workshops, training in the responsible conduct of research, seminars and conferences. The candidate also proposes to gain experience in operating an independent research lab through grant writing workshops, networking and mentorship from a multidisciplinary advisory committee with expertise in obstetrics, reproductive sciences, neonatology, infectious disease and chemical biology/pharmacology, whom have long track records in training future independent researchers. The work in K99 phase will be completed at Vanderbilt University Medical Center, which has a plethora of resources and expertise available that perfectly aligned with the PI’s needs. The candidate`s primary goal is to establish a successful, independent research program that tests translational interventions aimed at management of infection-induced preterm labor (III-PTL). Preterm birth, defined as delivery before 37 weeks of gestation, is the leading worldwide cause of infant morbidity and mortality. Intrauterine infection and/or inflammation is a major trigger of early labor leading to preterm birth and fetal inflammation causing adverse neonatal outcomes. Unfortunately, there is a critical lack of therapeutics for the management of early labor that occurs as the result of infection/inflammation during pregnancy. Studies involved in the K99 and R00 phases of this proposal encompass novel approaches to identify effective therapeutic agents to manage III-PTL without adverse effects. Recent transcriptomic studies on gestational membranes have identified gene targets implicated in III-PTL and we have determined which of these genes are part of the druggable genome and could be explored for therapeutic regulation of III-PTL. In Aim 1 (K99) we will optimize a high-throughput screening (HTS) assay to measure changes in proinflammatory cytokines released from pathogen-associated molecular patterns (PAMP)-induced gestational membrane (GM) explants in 96-well format. We will utilize this HTS assay to screen a customized library of small-molecules that target the druggable transcriptome associated with III-PTL. We will perform a series of secondary screens to prioritize hit-molecules into leads. In Aim 2 (R00 phase), we will utilize a high-throughput combination screen to identify combination therapeutics with synergistic effects. In Aim 3 (R00 phase), mouse models of III-PTL will be used to confirm the in vivo ability of our lead-single or synergistic combinations to manage PTL and protect against fetal inflammation. The training plan and outstanding mentoring committee will ensure the success of the project and support the candidate’s career development towards the establishment of an independent research lab in the R00 phase.

项目摘要 在此K99/R00独立应用途径中，候选人提议结构化，严格和 详细的培训计划，建立在体内妊娠组织建模和早产生理学方面的专业知识 在最新的药物发现方法中继续教育。该培训计划将得到支持 动手培训，课程，讲习班，负责任的研究，半手和培训 会议。候选人还建议通过 授予具有专业知识的多学科咨询委员会的授予写作讲习班，网络和心态 在妇产科，生殖科学，新生儿学，传染病和化学生物学/药理学领域 在培训未来的独立研究人员中有很长的记录。 K99阶段的工作将在 范德比尔特大学医学中心，拥有大量的资源和专业知识，非常完美 与Pi的需求保持一致。候选人的主要目标是建立成功的独立研究 测试旨在管理感染引起的早产劳动（III-PTL）的转化干预措施的计划。 早产是在妊娠37周之前定义为分娩的，是全球的主要原因 发病率和死亡率。介绍性感染和/或感染是早期劳动的主要触发因素，导致 早产和胎儿感染导致不良新生儿结局。不幸的是，存在严重的缺乏 在感染/炎症期间发生的早期劳动管理的理论 怀孕。该提案的K99和R00阶段涉及的研究涵盖了新方法来识别 有效管理III-PTL而不会产生不良影响的治疗剂。最近的转录组研究 妊娠膜已经确定了在III-PTL中实施的基因靶标，我们已经确定了其中哪个基因靶标 基因是可药物基因组的一部分，可以探索用于III-PTL的治疗调节。在目标1中 （K99）我们将优化高通量筛选（HTS）测定以测量促炎的变化 从病原体相关的分子模式（PAMP）诱导的妊娠膜（GM）释放的细胞因子 外植物的96孔格式。我们将利用此HTS测定法筛选一个定制的小分子库 靶向与III-PTL相关的可药物转录组。我们将执行一系列辅助屏幕 将命中分子确定为铅。在AIM 2（R00阶段）中，我们将使用高通量组合屏幕 确定结合疗法与协同作用。在AIM 3（R00相）中，III-PTL的鼠标模型将为 用于确认我们的铅铅或协同组合管理PTL和保护的体内能力 反对胎儿炎症。培训计划和杰出的心理委员会将确保 该项目并支持候选人的职业发展，以建立独立 R00阶段的研究实验室。