Investigations of antiretroviral therapy penetration in cerebrospinal fluid

抗逆转录病毒疗法在脑脊液中渗透的研究

• 批准号: 10259176
• 负责人: Sean Avedissian
• 金额: $ 17.04万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-05 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10259176
• 关键词: AIDS clinical trial group; AIDS dementia; Address; Age; Agreement; Anatomy; Animal Model; Animals; Anti-Retroviral Agents; Antiviral Agents; Award; Basic Science; Biological Assay; Blood; Blood - brain barrier anatomy; Brain; CCL2 gene; Cell model; Cerebrospinal Fluid; Characteristics; Clinical; Clinical Pharmacology; Clinical Research; Cohort Studies; Data; Detection; Development; Discipline of Nursing; Doctor of Philosophy; Drug Exposure; Drug Kinetics; Drug usage; Ensure; Ethics; Excretory function; Exposure to; Extramural Activities; Faculty; Foxes; Functional disorder; Funding; Future; Goals; HIV; HIV Infections; HIV-associated neurocognitive disorder; Hand; Human; Human body; IL6 gene; Immune response; In Vitro; Individual; Institution; Investigation; Life Expectancy; Link; Liquid substance; Literature; Measures; Medical center; Mental disorders; Mentored Patient-Oriented Research Career Development Award; Mentors; Metabolism; Mission; Monkeys; NCI Scholars Program; Names; National Institute of Mental Health; Nebraska; Neopterin; Neuraxis; Neurocognitive; Neurocognitive Deficit; Neurologic; Participant; Pathogenesis; Pathway interactions; Patients; Penetration; Performance; Pharmaceutical Preparations; Pharmacology; Physiological; Plasma; Population; Prevention; Primates; Principal Investigator; Property; RNA; Recovery; Regimen; Reporting; Research; Research Personnel; Research Project Grants; Research Proposals; SIV; Sampling; Scientist; Severities; Structure; Techniques; Testing; Therapeutic; Tissue Sample; Tissues; Training; Translational Research; Translations; United States National Institutes of Health; Universities; Viral; Viral Load result; Viral reservoir; Virus; Work; absorption; antiretroviral therapy; base; brain endothelial cell; career; career development; clinically significant; co-infection; cohort; college; comorbidity; design; didactic education; experimental study; high risk; improved; in vitro Model; in vivo; innovation; interpatient variability; member; memory CD4 T lymphocyte; monolayer; multidisciplinary; neuroinflammation; novel; novel strategies; older patient; optimal treatments; patient oriented research; personalized medicine; pharmacokinetic model; pharmacokinetics and pharmacodynamics; professor; programs; prospective; response; responsible research conduct; skills; sound; translational scientist; virology

Name of Principal Investigator: Sean N. Avedissian Project Summary I am applying for a Mentored Patient-Oriented Research Career Development Award (NIMH-K23) for training in patient- oriented research with the goal of development into a productive and independent clinical and translational researcher. As part of this award, I will complete a PhD in Clinical Translational Research (CTR) through the mentored scholar’s program at my institution, University of Nebraska Medical Center (UNMC). This PhD program does not compete with the K23. The members of my mentoring team are Drs. Courtney V. Fletcher, Howard Fox, Kimberly Scarsi and Susan Swindells, all recognized leaders in HIV with expertise in all aspects of this research proposal. Dr. Fletcher will serve as my primary mentor and will guide and facilitate continued training in HIV pharmacology as well as in responsible conduct of research (RCR). The overall aim of the didactic training/PhD program is to provide multidisciplinary didactic education and practical research grant training to junior faculty like myself, who intend to develop a career in CTR, so they may acquire the skills to design, implement, analyze and report ethically sound, extramurally funded CTR. The PhD program is intended to serve as a pathway to accelerate the career development of junior faculty members. The director of the CTR-MSP is Dr. Lani Zimmerman, Professor in the College of Nursing at UNMC. My research will focus on investigation of fundamental characteristics of antiretroviral penetration into the central nervous system (CNS) using in vitro and animal models, with confirmation of penetration properties in people with HIV, followed by development and translation of a new approach to assess the anti-HIV activity of an entire antiretroviral regimen (as opposed to just that of an individual drug). The long-term goal is to develop novel strategies to achieve complete viral cure in all reservoirs of people with HIV. This proposal is clinically significant because HIV is known to persist in the brain, even in patients receiving potent antiretroviral regimens, who are highly adherent and have undetectable plasma HIV viral load. Given advancements in HIV therapeutics, people with HIV are older due to longer life expectancies(1, 2). However, even with advancements in HIV therapeutics, the rates of HIV-associated brain disturbances continue to remain high(3). Emerging evidence suggests that older patients with HIV may be at an even higher risk of developing HIV-associated neurocognitive dysfunction due to age and viral burden in the CSF(4, 5). Thus, there is an unmet need for improved personalized medicine approaches directed towards maximizing antiviral exposures to decrease viral burden throughout the whole body. Importantly, the goals of my research address the neurologic complications focus component of the current NIH Priorities for HIV and HIV-Related Research which is to “Address HIV-Associated Comorbidities, Coinfections and Complications”. On completion of the award period, I will have acquired the expertise to conduct independent research in CNS focused HIV pharmacology. I will have completed in-depth training in HIV and CNS translational and clinical research, allowing me to become an independent clinical scientist and leader in the field of HIV viral reservoir related pharmacology.

主要研究者姓名：Sean N.阿韦迪西安 项目摘要 我正在申请一个指导病人为导向的研究职业发展奖（NIMH-K23）的培训病人- 以研究为导向，目标是发展成为一个富有成效的和独立的临床和翻译研究人员。作为 作为该奖项的一部分，我将通过导师计划完成临床转化研究（CTR）博士学位 内布拉斯加大学医学中心（UNMC）这个博士课程不与K23竞争。 我的指导团队的成员是考特尼V.弗莱彻博士，霍华德福克斯，金伯利斯卡西和苏珊斯温德尔斯，所有 艾滋病毒领域公认的领导者，他们在这项研究提案的各个方面都有专门知识。弗莱彻医生将担任我的首席 指导并将指导和促进艾滋病毒药理学方面的持续培训以及负责任地开展研究 （RCR）。 教学培训/博士课程的总体目标是提供多学科教学教育和实践研究 向像我这样打算在CTR发展职业生涯的初级教师提供培训，这样他们就可以获得设计技能， 实施、分析和报告道德上健全的、外部资助的CTR。博士课程旨在作为一个 加速初级教师职业发展的途径。CTR-MSP的主任是Lani博士 齐默尔曼，联合国大学护理学院教授。 我的研究将集中在抗逆转录病毒药物渗透到中枢神经系统的基本特征的调查 系统（CNS）使用体外和动物模型，确认在艾滋病毒感染者中的渗透特性， 通过开发和翻译一种新的方法来评估整个抗逆转录病毒治疗方案的抗HIV活性（如 而不仅仅是单个药物）。长期目标是开发新的策略以实现完全的病毒治愈 在所有艾滋病病毒携带者中。这一提议具有临床意义，因为已知艾滋病毒会持续存在于大脑中， 即使在接受强效抗逆转录病毒治疗的患者中， 即可.鉴于艾滋病毒治疗的进步，艾滋病毒感染者由于预期寿命较长而年龄较大（1，2）。然而，在这方面， 即使在HIV治疗方面取得了进步，HIV相关脑功能障碍的发生率仍然很高（3）。 新出现的证据表明，年龄较大的艾滋病毒感染者发生艾滋病毒相关性疾病的风险可能更高。 由于年龄和CSF中的病毒负荷导致的神经认知功能障碍（4，5）。因此，存在未满足的改进的需求。 个体化的药物治疗方法，旨在最大限度地提高抗病毒药物的暴露量， 全身重要的是，我的研究目标是解决神经并发症的重点组成部分， 目前NIH HIV和HIV相关研究的优先事项是“解决HIV相关的合并症， 合并感染和并发症”。 在奖励期结束后，我将获得专门知识，在中枢神经系统重点艾滋病毒进行独立研究 药理学我将完成HIV和CNS转化和临床研究方面的深入培训， 成为HIV病毒库相关药理学领域的独立临床科学家和领导者。