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.

项目概要 在这份 K99/R00 独立之路申请中，候选人提出了一个结构化、严格和 详细的培训计划，以建立离体妊娠组织建模和早产生理学方面的专业知识 该培训计划将通过最新药物发现方法的持续教育得到支持。 实践培训、课程、讲习班、负责任地进行研究的培训、研讨会和 候选人还建议通过会议获得运营独立研究实验室的经验。 来自具有专业知识的多学科咨询委员会的拨款写作研讨会、网络和指导 在产科、生殖科学、新生儿学、传染病和化学生物学/药理学领域， 在培训未来独立研究人员方面拥有长期记录。K99 阶段的工作将于 范德比尔特大学医学中心拥有丰富的资源和专业知识，可以完美地满足您的需求。 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的转化干预措施的计划（III-PTL）。 早产，定义为妊娠 37 周之前分娩，是全球婴儿出生的主要原因 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。 不幸的是，早产和胎儿炎症导致新生儿不良结局严重缺乏。 治疗因感染/炎症而发生的早产的治疗方法 该提案的 K99 和 R00 阶段涉及的研究包括识别怀孕的新方法。 治疗 III-PTL 的有效治疗剂，且无副作用。 妊娠膜已鉴定出与 III-PTL 相关的基因靶标，我们已确定其中哪些 基因是可药物基因组的一部分，可用于探索 III-PTL 的治疗调节 In Aim 1。 （K99）我们将优化高通量筛选（HTS）测定法来测量促炎性变化 病原体相关分子模式 (PAMP) 诱导的妊娠膜 (GM) 释放的细胞因子 我们将利用这种 HTS 测定来筛选定制的小分子文库。 我们将针对与 III-PTL 相关的可成药转录组进行一系列二次筛选。 在 Aim 2（R00 阶段）中，我们将利用高通量组合筛选将命中分子优先排序。 确定具有协同效应的治疗组合 在 Aim 3（R00 阶段）中，将建立 III-PTL 小鼠模型。 用于确认我们的单一先导化合物或协同组合在体内管理 PTL 和保护的能力 对抗胎儿炎症的培训计划和优秀的指导委员会将确保此次培训的成功。 该项目并支持候选人的职业发展，以建立独立的 R00阶段的研究实验室。