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: 10577752
• 负责人: Sean Avedissian
• 金额: $ 17.31万
• 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/10577752
• 关键词: AIDS clinical trial group; AIDS dementia; Acceleration; Address; Age; Agreement; Anatomy; Animal Model; Animals; Anti-Retroviral Agents; Award; Basic Science; Biological Assay; Blood; Brain; CCL2 gene; Cell model; Central Nervous System; 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; 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; Names; National Institute of Mental Health; Nebraska; Neopterin; Neurocognitive; Neurocognitive Deficit; Neurologic; Participant; Pathogenesis; Pathway interactions; Patients; Penetration; Performance; Persons; Pharmaceutical Preparations; Pharmacology; Physiological; Plasma; Population; Prevention; Primates; Principal Investigator; Productivity; Property; RNA; Recovery; Regimen; Reporting; Research; Research Personnel; Research Project Grants; Research Proposals; SIV; Sampling; Scholars Program; 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; blood-brain barrier crossing; brain endothelial cell; career; career development; clinical translation; 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; patient variability; personalized medicine; pharmacokinetic model; pharmacokinetics and pharmacodynamics; pharmacologic; professor; programs; prospective; response; responsible research conduct; skill acquisition; sound; translational scientist

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.

首席研究员的名称：Sean N. Avedissian 项目摘要 我正在申请一个受过指导的以患者为导向的研究职业发展奖（NIMH-K23），以培训患者 - 以发展为生产性和独立临床和翻译研究人员的目标研究。作为 该奖项的一部分，我将通过指导科学计划完成临床转化研究（CTR）博士学位 在我的机构，内布拉斯加州大学医学中心（UNMC）。该博士学位计划与K23没有竞争。 我的指导团队的成员是Drs。考特尼·V·弗莱彻，霍华德·福克斯，金伯利·斯卡萨斯和苏珊·斯温德斯都 公认的艾滋病毒领导者在这项研究建议的各个方面具有专业知识。弗莱彻博士将担任我的主要 Menor并将指导并促进继续接受HIV药理学以及负责任的研究的培训 （RCR）。 教学培训/博士学位计划的总体目的是提供多学科的教学教育和实践研究 授予像我这样的初级教师的培训，他们打算在CTR中发展职业，因此他们可能会获得设计技能， 实施，分析和报告道德上有声音的CTR，外部资助的CTR。博士课程旨在作为 加速初级教师职业发展的途径。 CTR-MSP的主任是Lani博士 Zimmerman，UNMC护理学院的教授。 我的研究将集中于抗逆转录病毒渗透到中枢神经的基本特征的投资 使用体外和动物模型的系统（CNS），并确认HIV患者的穿透性特性 通过开发和翻译新方法来评估整个抗逆转录病毒方案的抗HIV活性（AS 仅反对单个药物）。长期目标是制定新的策略以实现完整的病毒治疗 在所有艾滋病毒的人的水库中。该建议具有临床意义，因为已知HIV持续存在于大脑中， 即使在接受潜在抗逆转录病毒方案的患者中，他们具有高度依从性并且具有无法检测的血浆HIV病毒 加载。鉴于艾滋病毒疗法的进步，由于预期寿命较长，艾滋病毒患者年龄较大（1、2）。然而， 即使随着艾滋病毒治疗方面的进步，与艾滋病毒相关的脑疾病的发生率仍然很高（3）。 新兴的证据表明，艾滋病毒的老年患者可能患有与HIV相关的更高风险 CSF中年龄和病毒灼伤引起的神经认知功能障碍（4，5）。那是没有满足的改进需求 个性化医学方法是针对最大化抗病毒暴露以减轻整个病毒负担的 全身。重要的是，我的研究目标涉及神经系统并发症的重点部分 当前的NIH艾滋病毒和艾滋病毒相关研究的重点是“解决与艾滋病毒相关的合并症， 共同感染和并发症”。 颁奖期结束后，我将获得专业知识，以在CNS以CNS为中心的HIV进行独立研究 药理。我将完成艾滋病毒和中枢神经系统转化和临床研究的深入培训，使我能够 成为HIV病毒参与者相关药理学领域的独立临床科学家和领导者。