Mentoring Investigators in HIV and Tuberculosis Therapeutics Research

摘要 结核病(TB)现在是全球主要的传染病死亡原因，它仍然是头号致死原因。 艾滋病毒感染者(PLWH)死亡。一线治疗方案对患者来说既长又重 耐药结核病通常需要1-2年的药物治疗，这些药物可能会导致 严重的或不可逆转的毒性。结核病药物开发渠道现在是强大的，提供了理由 乐观主义。然而，为了优化现有药物和新药，我们必须使用最先进的药物 发展方法(包括最佳利用定量药理学)，当务之急是 开发药物或方案，以便它们可以用于所有可能从中受益的患者， 包括妇幼保健院、儿童和孕妇。关键的挑战和机遇在于使用 临床药理学作为结核病和艾滋病毒治疗研究中更有效的工具，跨药物 开发和优化频谱。这是K24职业生涯中期申请的背景 Kelly Dooley，医学博士，医学、药理学和医学副教授 约翰霍普金斯大学临床药理学和传染病学部的分子科学 大学，提供受保护的时间，指导以患者为导向的结核病和艾滋病毒研究学员 治疗学。杜利医生是少数受过临床培训的传染病专家之一 从事结核病治疗领域的药理学研究。她是全球公认的结核病和艾滋病毒领域的领导者- 与结核病治疗相关的研究，并指导(并正在指导)该领域的多名受训人员。 通过她领导的多个独立资助的研究以及她在 作为ACTG、TBTC和IMPAACT结核病科学领导委员会成员的能力 网络，她能够提供极好的机会来培训下一代临床医生 以病人为中心的结核病和艾滋病毒研究的研究人员。此外，这款K24将允许她扩展她的 自己在几个关键领域的知识：定量药理学方法，应用于设计和 结核病或结核病-艾滋病毒治疗临床试验中的分析；生物标志物的识别和使用以及 了解将药物输送到难以接近的隔室，例如在结核性脑膜炎中； 和一个关键的未得到满足的医疗需求的新领域，非结核分枝杆菌的治疗(in 携带和不携带艾滋病毒的患者)。这辆K24将允许杜利博士有保障的时间来训练下一名 一代临床药理学和临床研究的研究人员，用于结核病和艾滋病毒- 相关结核病是一个严重短缺的领域；扩大结核病治疗工作中的量化方法；以及 探索新的调查领域。这一奖项提供的保护时间对杜利博士来说是至关重要的 实现这些目标。

SUMMARY Tuberculosis (TB) is now the leading infectious cause of death globally, and it remains the #1 cause of death among people living with HIV (PLWH). The first-line regimen is long and burdensome to patients and programs, and drug-resistant TB typically requires treatment for 1-2 years with drugs that can cause severe or irreversible toxicities. The TB drug development pipeline is now robust, providing reason for optimism. To optimize current and new drugs, though, we must employ state-of-the-art drug development approaches (including best use of quantitative pharmacology), and it is imperative that new drugs or regimens be developed so that they can be used in all patients that may benefit from them, including PLWH, children, and pregnant women. Critical challenges and opportunities lie in using clinically pharmacology as a tool more effectively in TB and HIV therapeutics research, across the drug development and optimization spectrum. This is the context for this application for a K24 Mid-Career Development Award for Kelly Dooley, MD, PhD, Associate Professor of Medicine, Pharmacology, & Molecular Sciences in the Divisions of Clinical Pharmacology and Infectious Diseases at Johns Hopkins University, to provide protected time to mentor trainees in patient-oriented research in TB and HIV therapeutics. Dr. Dooley is one of the few Infectious Diseases specialists with training in Clinical Pharmacology working in the TB therapeutics field. She is a globally-recognized leader in TB and HIV- associated TB treatment research and has mentored (and is mentoring) multiple trainees in the field. Through the multiple independently-funded studies she is leading as well as those she is directing in her capacity as a member of the TB scientific leadership committees of the ACTG, TBTC, and IMPAACT networks, she is in a position to provide excellent opportunities to train the next generation of clinical researchers in patient-oriented research in TB and HIV. In addition, this K24 will allow her to expand her own knowledge in several key areas: quantitative pharmacology approaches, as applied to design and analysis in clinical trials of TB or TB-HIV treatment; biomarkers identification and use as well as understanding of drug delivery to hard-to-access compartments, for example in tuberculous meningitis; and a new area of critical unmet medical need, the treatment of nontuberculous mycobacteria (in patients with and without HIV). This K24 will allow Dr. Dooley to have the protected time to train the next generation of investigators in clinical pharmacology and clinical research, as applied to TB and HIV- associated TB, a critical shortage area; expand quantitative approaches in TB therapeutics work; and explore new areas of investigation. The protected time afforded by this award is essential to Dr. Dooley achieving these goals.