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: 10364740
• 负责人: Sean Avedissian
• 金额: $ 17.3万
• 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/10364740
• 关键词: AIDS clinical trial group; AIDS dementia; Address; Age; Agreement; Anatomy; Animal Model; Animals; Anti-Retroviral 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; Persons; 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

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.

首席研究员姓名：Sean N. Avedissian 项目概要 我正在申请以患者为导向的研究职业发展奖 (NIMH-K23)，以进行患者培训： 以研究为导向，目标是发展成为一名富有成效、独立的临床和转化研究人员。作为 作为该奖项的一部分，我将通过指导学者计划完成临床转化研究 (CTR) 博士学位 在我所在的机构内布拉斯加大学医学中心 (UNMC)。该博士项目不与 K23 竞争。 我的指导团队的成员是博士。考特尼·V·弗莱彻 (Courtney V. Fletcher)、霍华德·福克斯 (Howard Fox)、金伯利·斯卡西 (Kimberly Scarsi) 和苏珊·斯温德尔 (Susan Swindells) 公认的艾滋病毒领域的领导者，在本研究提案的各个方面都具有专业知识。弗莱彻博士将担任我的主要 导师并将指导和促进艾滋病毒药理学以及负责任的研究行为的持续培训 （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 为像我这样打算在 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、 实施、分析和报告道德合理、外部资助的 CTR。该博士课程旨在作为 加快青年教师职业发展的途径。 CTR-MSP 的主任是 Lani 博士 Zimmerman，UNMC 护理学院教授。 我的研究重点是研究抗逆转录病毒渗透到中枢神经的基本特征 系统（CNS）使用体外和动物模型，并确认了艾滋病毒感染者的渗透特性，随后 通过开发和转化一种新方法来评估整个抗逆转录病毒疗法的抗艾滋病毒活性（如 与单一药物相反）。长期目标是开发新策略以实现病毒的彻底治愈 所有艾滋病病毒感染者的储存库。这项提议具有临床意义，因为已知艾滋病毒会持续存在于大脑中， 即使是接受强效抗逆转录病毒疗法的患者，他们的依从性很高且血浆 HIV 病毒检测不到 加载。鉴于艾滋病毒治疗方法的进步，艾滋病毒感染者的预期寿命更长，因此年龄也更大(1, 2)。然而， 即使艾滋病毒疗法取得了进步，艾滋病毒相关脑部紊乱的发生率仍然很高(3)。 新的证据表明，老年艾滋病毒感染者患艾滋病毒相关疾病的风险可能更高 由于年龄和脑脊液病毒负荷导致的神经认知功能障碍(4, 5)。因此，对于改进的需求尚未得到满足 个性化医疗方法旨在最大限度地增加抗病毒药物暴露，以减少整个过程中的病毒负担 全身。重要的是，我的研究目标是解决神经系统并发症的重点组成部分 目前 NIH 的 HIV 和 HIV 相关研究优先事项是“解决 HIV 相关合并症、 合并感染和并发症”。 奖励期结束后，我将获得针对中枢神经系统艾滋病毒进行独立研究的专业知识 药理。我将完成艾滋病毒和中枢神经系统转化和临床研究方面的深入培训，使我能够 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。