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