Novel Imaging and host-directed therapy in pediatric CNS TB

项目总结：中枢神经系统（CNS）结核病（TB），最常见的是结核性脑膜炎（TBM）， 结核病是最严重的一种结核病，对儿童的影响尤为严重， 治疗后的一半。目前的治疗是不够的-它是基于肺结核，不是最佳的中枢神经系统 渗透并且不能充分改善引起神经损伤的神经炎症。K 08奖 将为约翰霍普金斯大学的儿科重症监护医生塔克博士提供必要的时间、培训和资源 和指导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， 了解宿主免疫反应导致脑损伤的TBM，以告知抗菌和预防 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，Tucker博士将使用幼年TBM兔模型 研究以下目的：（1）优化新的结核病抗微生物药物在感染部位的剂量，（2） 确定是否有程度的细菌负荷，炎症或抗菌剂渗透的部位， 使用多模态正电子发射断层扫描（PET），感染与神经系统结局最相关 成像，和（3）确定是否有针对性的宿主，抗氧化治疗（树枝状聚合物-N-乙酰基-L- 半胱氨酸[NAC]）可减弱神经炎症并改善神经损伤。到 为了实现她的长期目标，完成她的K 08目标，塔克博士组建了一个跨学科的 由经验丰富的调查人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; 博士Sujatha Kannan是儿科重症监护医学教授，其研究重点是调查 神经炎症在大脑发育中的作用和纳米疗法的利用，Sanjay Jain博士是 一位儿科传染病和放射学教授，他是TBM和新药物开发方面的专家。 PET成像示踪剂。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作用： 纳米医学，质谱和药物计量学，为她的培训提供坚实的基础。五个- 一年的职业发展计划将提供神经病理学，免疫学，药理学，代谢组学的培训 和生物统计学，以完成这些目标，并导致未来的R 01应用，以研究治疗 改善儿童结核性脑膜炎预后的策略。完成拟议的研究将 显著地推进了我们对细菌负荷、宿主免疫和免疫应答之间的动态相互作用的认识。 反应和抗菌剂在感染部位的渗透，并提供了新的见解TBM的发病机制。 此外，这项研究将为临床翻译提供基础，以优化CNS感染的治疗 与药代动力学建模和树枝状聚合物纳米器件，以提高中枢神经系统药物输送以及新的 非侵入性成像以监测治疗反应。几种新的PET示踪剂和树枝状聚合物-NAC已经在 正在进行首次人体研究或临床试验，以增强对患者的转化。

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.