Discovery of Novel Therapeutics for Inflammation Induced Preterm Birth

项目摘要 在这个K99/R 00独立之路应用程序中，候选人提出了一个结构化的，严谨的， 详细的培训计划，以建立体外妊娠组织建模和早产生理学方面的专业知识，沿着 在最新的药物发现方法方面继续接受教育。该培训计划将得到以下方面的支持： 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 两会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 由具有专门知识的多学科咨询委员会举办赠款编写讲习班、建立联系和提供指导 在产科、生殖科学、妇科学、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着长期的记录。K99阶段工作将于 范德比尔特大学医学中心拥有大量的资源和专业知识， 符合私家侦探的需求候选人的主要目标是建立一个成功的，独立的研究 该计划旨在测试旨在管理感染性早产（III-PTL）的转化干预措施。 早产，定义为妊娠37周之前分娩，是世界范围内婴儿死亡的主要原因。 发病率和死亡率。子宫内感染和/或炎症是导致早产的主要触发因素， 早产和胎儿炎症导致不良新生儿结局。不幸的是， 用于管理由于在分娩过程中感染/炎症而发生的早期分娩的治疗方法 怀孕本提案的K99和R 00阶段涉及的研究包括新的方法， 有效的治疗剂来管理III-PTL而没有副作用。转录组学研究进展 妊娠膜已经确定了与III-PTL有关的基因靶点，我们已经确定了这些基因中的哪一个， 基因是可药物化基因组的一部分，并且可以探索用于III-PTL的治疗调节。目标1 (K99)我们将优化高通量筛选（HTS）试验，以测量促炎性细胞因子的变化， 病原体相关分子模式（PAMP）诱导的妊娠膜（GM）释放的细胞因子 96孔格式的外植体。我们将利用这种HTS测定来筛选定制的小分子文库， 靶向与III-PTL相关的可药用转录组。我们将进行一系列的二次筛选， 将命中分子按优先级排列成线索。在目标2（R 00阶段），我们将利用高通量组合筛选， 鉴定具有协同作用组合治疗剂。在目标3（R 00阶段），将建立III-PTL小鼠模型。 用于证实我们的铅单一或协同组合的体内能力，以管理PTL和保护 对抗胎儿炎症培训计划和优秀的指导委员会将确保 项目，并支持候选人的职业发展，建立一个独立的 R 00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.