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.

首席调查员姓名：肖恩·N·阿维迪辛 项目摘要 我正在申请以患者为导向的导师研究职业发展奖(NIMH-K23)，以培训患者- 面向研究，目标是发展成为多产的、独立的临床和翻译研究人员。AS 作为这一奖项的一部分，我将通过指导学者计划完成临床转化研究(CTR)博士学位 在我的机构，内布拉斯加大学医学中心(UNMC)。这个博士项目不与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，他们都是 在这项研究提案的所有方面都具有专业知识的公认的艾滋病毒领域的领导者。弗莱彻医生将担任我的首席医生 指导并将指导和促进艾滋病毒药理学以及负责任的研究工作的持续培训 (RCR)。 教学培训/博士课程的总体目标是提供多学科的教学教育和实践研究 为像我这样打算在CTR发展事业的初级教员提供培训，这样他们就可以获得设计技能， 执行、分析和报告合乎道德规范的、外部资助的CTR。博士课程的目的是作为一种 促进初级教职员工职业发展的途径。CTR-MSP的主任是拉尼博士 UNMC护理学院教授齐默尔曼说。 我的研究将集中在研究抗逆转录病毒渗透到中枢神经系统的基本特征 使用体外和动物模型的系统(CNS)，确认了艾滋病毒携带者的渗透特性，随后 通过开发和翻译一种新的方法来评估整个抗逆转录病毒方案(AS)的抗HIV活性 而不是仅仅针对某一种药物)。长期目标是开发新的策略来实现彻底治愈病毒 在所有艾滋病毒携带者的水库中。这一建议具有临床意义，因为已知艾滋病毒会在大脑中持续存在， 即使在接受有效抗逆转录病毒疗法的患者中，他们也是高度依从性的，并且血浆中艾滋病毒病毒检测不到 装填。鉴于艾滋病毒治疗的进步，艾滋病毒携带者由于预期寿命更长而年龄更大(1，2)。然而， 即使艾滋病毒治疗方法取得了进步，艾滋病毒相关脑部疾病的发生率仍然居高不下(3)。 新的证据表明，老年艾滋病毒携带者患艾滋病毒相关疾病的风险可能更高。 年龄和脑脊液病毒负荷引起的神经认知功能障碍(4，5)。因此，对改进的需求还没有得到满足。 个性化医疗方法旨在最大限度地增加抗病毒暴露，以减少整个 全身上下。重要的是，我的研究目标是解决神经并发症的焦点部分 目前国立卫生研究院艾滋病毒和艾滋病毒相关研究的优先事项是“解决艾滋病毒相关的合并症， 合并感染和并发症“。 在获奖期结束时，我将获得在以中枢神经系统为重点的艾滋病毒方面进行独立研究的专业知识 药理学。我将完成HIV和CNS翻译和临床研究的深入培训，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。