Discovery of Novel Therapeutics for Inflammation Induced Preterm Birth

项目总结 在这份K99/R00通向独立之路的申请中，候选人提出了一个有条理、严谨和 详细的培训计划，以积累体外妊娠组织建模和早产生理学方面的专业知识 在药物发现的最新方法方面进行持续教育。该培训计划将通过以下方式得到支持 实践培训、课程作业、讲习班、负责任地开展研究的培训、研讨会和 会议。候选人还建议通过以下方式获得运营独立研究实验室的经验 授予写作研讨会、网络和来自具有专业知识的多学科咨询委员会的指导 在产科、生殖科学、新生儿学、传染病和化学生物学/药理学方面， 在培养未来的独立研究人员方面有长期的记录。K99阶段的工作将于 范德比尔特大学医学中心，该中心拥有丰富的资源和专业知识 与PI的需求保持一致。候选人的首要目标是建立一项成功的、独立的研究 测试旨在管理感染诱发早产(III-PTL)的翻译干预措施的计划。 早产，定义为怀孕37周前分娩，是全球婴儿的主要原因 发病率和死亡率。宫内感染和/或炎症是导致早产的主要诱因 早产和胎儿炎症会导致不良的新生儿结局。不幸的是，有一个严重的缺乏 治疗因感染/炎症引起的早产 怀孕了。该提案的K99和R00阶段涉及的研究包含了新的方法，以确定 有效的治疗药物来管理III-PTL而不会有不良反应。最新的转录转录研究 妊娠膜已经确定了与III-PTL有关的基因靶点，我们已经确定了其中哪些 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查(HTS)分析，以测量促炎症变化 病原体相关分子模式(PAMP)诱导的妊娠膜(GM)释放细胞因子 96孔格式的外植体。我们将利用这种HTS试验来筛选一个定制的小分子文库， 靶向与III-PTL相关的可药物转录组。我们将进行一系列的二级筛选，以 将命中分子优先排序为线索。在目标2(R00阶段)中，我们将利用高通量组合筛选来 确定具有协同作用的联合疗法。在AIM 3(R00阶段)，III-PTL的小鼠模型将是 用于确认我们的铅-单一或协同组合在体内管理PTL和保护的能力 对抗胎儿炎症。培训计划和优秀的指导委员会将确保 该项目和支持候选人的职业发展朝着建立独立的 处于R00阶段的研究实验室。

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.