Novel Imaging and host-directed therapy in pediatric CNS TB

项目简介：中枢神经系统(CNS)结核病(TB)，最常见的结核病脑膜炎(TBM)， 结核病是一种最严重的结核病，对儿童的影响不成比例，导致超过1000人的死亡或神经功能障碍。 尽管接受了治疗，还是有一半的人。目前的治疗是不够的-它是基于肺结核病的，没有针对中枢神经系统进行优化 穿透，并不能充分改善导致神经损伤的神经炎症。K08大奖 将为约翰·霍普金斯大学的儿科重症医生塔克博士提供必要的时间、培训和资源 和导师来实现她的目标。她的长期目标是成为一名独立的临床科学家，以更好地 了解TBM致脑损伤的宿主免疫反应，为抗菌药物和辅助剂提供信息 治疗策略，并设计治疗监测工具，以改善治疗和预后 患有这种毁灭性疾病的儿童。在目前的提案中，塔克博士将使用一种幼年的TBM兔模型 目的：(1)优化结核病新抗菌药物在感染部位的用药剂量；(2) 确定感染部位的细菌负荷、炎症或抗菌剂渗透程度 应用多模式位置发射断层扫描(PET)研究感染与神经系统预后的相关性 成像，以及(3)确定辅助宿主指导的抗氧化治疗(树枝状大分子-N-乙酰-L- 以激活的小胶质细胞为靶点的半胱氨酸[NAC]可减轻神经炎症并改善神经损伤。至 实现她的长期目标和完成她的K08目标，塔克博士已经组建了一个跨学科的 由经验丰富的调查员组成的导师团队致力于她的成功。她的导师都是各自领域的专家； Sujatha Kannan博士是儿科重症监护医学教授，其研究重点是 神经炎症在大脑发育中的作用和纳米疗法的应用，Sanjay Jain博士是 一位儿童传染病和放射学教授，TBM和新药开发专家 宠物成像追踪器。此外，她的咨询委员会通过以下方面的专业知识加强了她的指导 纳米医学、质谱学和药物计量学为她的训练提供了坚实的基础。五个人- 一年的职业发展计划将提供神经病理学、免疫学、药理学、代谢组学方面的培训 和生物统计学，以完成这些目标，并导致未来的R01应用，以研究治疗 改善儿童TBM预后的策略。完成拟议的研究将 极大地提高了我们对细菌负荷、宿主免疫之间动态相互作用的了解 此外，我们还研究了感染部位的反应和抗菌素的渗透情况，并对TBM的发病机制提供了新的见解。 此外，本研究将为临床翻译提供基础，以优化中枢神经系统感染的治疗 通过药代动力学建模和树枝状大分子纳米器件来增强CNS药物传递以及新型 监测治疗反应的非侵入性成像。几种新型的PET示踪剂和树枝状大分子-NAC已经 正在进行首个人体研究或临床试验，以加强对患者的翻译。

PROJECT SUMMARY: Central nervous system (CNS) tuberculosis (TB), most often TB meningitis (TBM), is the most severe form of TB and disproportionately affects children, causing death or neurologic disability in over half despite treatment. Current treatment is inadequate – it is based on pulmonary TB, is not optimized for CNS penetration and does not sufficiently ameliorate the neuroinflammation causing neurologic injury. The K08 award will provide Dr. Tucker, a pediatric intensivist at Johns Hopkins University, the essential time, training, resources and mentorship to achieve her goals. Her long-term goal is to become an independent clinician scientist to better understand the host immune response resulting in brain injury in TBM, to inform antimicrobial and adjunctive therapeutic strategies, and to design therapeutic monitoring tools in order to improve treatment and prognosis of children with this devastating disease. In the current proposal, Dr. Tucker will use a juvenile TBM rabbit model to investigate the following aims: (1) optimize dosing of new TB antimicrobial drugs at the site of infection, (2) determine whether the degree of bacterial burden, inflammation or antimicrobial penetration at the site of infection correlates most with neurologic outcomes using multi-modality position emission tomography (PET) imaging, and (3) determine if adjunctive host-directed, anti-oxidative therapy (dendrimer-N-acetyl-L- cysteine[NAC]) targeted to activated microglia attenuates neuroinflammation and improves neurologic injury. To achieve her long-term goals and complete her K08 aims, Dr. Tucker has assembled an interdisciplinary mentorship team of experienced investigators committed to her success. Her mentors are experts in their fields; Dr. Sujatha Kannan is a Professor of Pediatric Critical Care Medicine, whose research focuses on investigating the role of neuroinflammation in the developing brain and utilization of nanotherapeutics, and Dr. Sanjay Jain is a Professor of Pediatric Infectious Disease and Radiology who is an expert in TBM and development of novel PET imaging tracers. Additionally, her advisory committee strengthens her mentorship with expertise in nanomedicine, mass spectrometry and pharmacometrics to provide a strong foundation for her training. The five- year career development plan will provide training in neuropathology, immunology, pharmacology, metabolomics and biostatistics in order to complete these aims and lead to future R01 applications to investigate therapeutic strategies that will improve the prognosis of children with TBM. Completion of the proposed research will significantly advance our knowledge of the dynamic interactions between bacterial burden, host immune response and antimicrobial penetration at the site of infection and provide new insights into TBM’s pathogenesis. Additionally, this research will provide a foundation for clinical translation to optimize treatment in CNS infections with pharmacokinetic modeling and dendrimer nanodevices to enhance CNS drug delivery as well as novel noninvasive imaging to monitor treatment response. Several novel PET tracers and dendrimer-NAC are already undergoing first-in-human studies or clinical trials which enhances translation to patients.