Aging with HIV: Novel Biomarkers of Inflammation and Morbidity

艾滋病毒引起的衰老：炎症和发病率的新生物标志物

• 批准号: 10463849
• 负责人: Carrie Down Johnston
• 金额: $ 19.48万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10463849
• 关键词: Advisory Committees; Age; Aging; Anti-Retroviral Agents; Back; Biological Markers; Biostatistical Methods; Blood; Caring; Cell Death; Cells; Cessation of life; Chronic; Clinical; Coculture Techniques; Cognition; DNA; Data; Elderly; Eugenia; Evaluation; Fostering; Foundations; Functional disorder; Gene Activation; Geriatrics; Geroscience; Goals; HIV; HIV Seronegativity; Immune; Immunology; Impaired cognition; In Vitro; Inflammation; Inflammatory; Institution; Interferons; Intervention; Investigation; Light; Link; Longitudinal Studies; Master' s Degree; Measurement; Measures; Mediating; Mediator of activation protein; Medical; Mentors; Mentorship; Mitochondrial DNA; Molecular; Morbidity - disease rate; Natural Immunity; Necrosis; Nested Case-Control Study; Neurocognitive; Neuropsychology; Oxides; Participant; Pattern; Performance; Pharmaceutical Preparations; Phenotype; Physical Function; Physical Performance; Physicians; Plasma; Plasma Cells; Ploidies; Process; Research; Research Design; Research Methodology; Research Personnel; Research Project Grants; Risk; Role; Scientist; Stress; Syndrome; Testing; Time; Training; Training Programs; Translational Research; Urine; Ursidae Family; Viral; Viremia; Visit; Weight; biobank; career; career development; clinical care; cognitive function; cognitive performance; cognitive testing; cohort; comorbidity; experience; experimental study; falls; frailty; high risk; immune activation; improved; inflammatory marker; insight; instrumental activity of daily living; mortality; novel marker; peer; sample collection; skills; success; tool; transcriptome sequencing; translational study; urinary

PROJECT SUMMARY/ABSTRACT The candidate’s career goal is to become an independent physician-scientist studying HIV and aging, and the increased burden of medical co-morbidities and geriatric syndromes in older adults with HIV (OAH). The candidate has laid the foundation for achieving this goal by gaining clinical expertise in caring for OAH, conducting research, and obtaining a Master’s Degree in Clinical and Translational Investigation. To achieve her career goal, the candidate will need to expand upon her geroscience and translational research skills, including additional biostatistics and research methods training which are described in this resubmission. A key component of the candidate’s training will be conducting the proposed research project. Despite effective antiretroviral medications, OAH bear a greater burden of medical co-morbidities and geriatric syndromes than their HIV-negative peers. Translational research investigating biomarkers inflammation offers as opportunity for insight to the process of accelerated/accentuated aging that is observed in OAH. Cell-free mitochondrial DNA (cfmtDNA) is released from cells undergoing stress and necroptosis-mediated cell death and has the potential to serve as a mediator and marker of chronic immune activation and dysregulation. We hypothesize that cfmtDNA will be associated with lower cognitive performance and greater frailty in a longitudinal study of OAH. Previously, we have studied a cohort of OAH (age 55 and over) at our institution, and those with cognitive impairment had higher average levels of cfmtDNA in plasma than participants without cognitive impairment. We propose to leverage this existing study to investigate the following specific aims: 1) Determine the association between cfmtDNA and cognition in OAH; 2) Determine the association between cfmtDNA and longitudinal physical function in OAH; and 3) Evaluate the immunostimulatory potential of cfmtDNA from OAH with and without cognitive decline. Participants from our existing cohort will be invited back for two study visits separated by 18-24 months, each visit will include detailed neurocognitive assessment, physical function measures, falls and instrumental and activities of daily living, and blood and urine specimen collection for analysis and creation of a biorepository. Together, these investigations will shed light on the relationship between cfmtDNA, immune activation and geriatric-related syndromes in OAH. This project proposes a five-year, multifaceted training program under the mentorship of Dr. Marshall Glesby as the primary mentor, as well as Drs. Mary Choi, Lishomwa Ndhlovu, and Eugenia Siegler as co-mentors. Together with a Scientific Advisory Committee, they will provide the expertise in research design, biomarkers, immunology and geroscience that will allow support the success of this project. The completion of the proposed project will lead to an enhanced understanding of cfmtDNA as a biomarker of geriatric syndromes in OAH, and a translational research tool to identify OAH at the highest risk of morbidity and mortality. After completion of this project, the candidate will be poised to submit a competitive R03 and R01 proposals.

项目总结/摘要 候选人的职业目标是成为一名独立的医学科学家，研究艾滋病毒和衰老， 老年艾滋病毒感染者的医疗合并症和老年综合征负担增加（OAH）。的 候选人通过获得护理OAH的临床专业知识，为实现这一目标奠定了基础， 进行研究，并获得临床和转化研究硕士学位。实现 她的职业目标，候选人将需要扩大她的老年科学和转化研究技能， 包括额外的生物统计学和研究方法培训，这些培训在本次重新提交中有所描述。 候选人培训的一个关键组成部分将是进行拟议的研究项目。尽管 有效的抗逆转录病毒药物，OAH承担了更大的医疗共病和老年病负担 比HIV阴性的同龄人更容易患上艾滋病。研究炎症生物标志物的转化研究提供了 作为深入了解OAH中观察到的加速/加重老化过程的机会。无细胞 线粒体DNA（cfmtDNA）从经历应激和坏死性凋亡介导的细胞死亡的细胞中释放 并且具有作为慢性免疫激活和失调的介质和标志物的潜力。 我们假设cfmtDNA将与低认知能力和更大的脆弱性相关， OAH的纵向研究。以前，我们在我们的机构研究了一组OAH（55岁及以上）， 而那些有认知障碍的人血浆中cfmtDNA的平均水平高于没有认知障碍的人。 认知障碍我们建议利用这项现有的研究来调查以下具体目标：1） 确定cfmtDNA与OAH中认知之间的关联; 2）确定cfmtDNA与OAH中认知之间的关联。 cfmtDNA和OAH的纵向身体功能;以及3）评估 cfmtDNA来自有和没有认知衰退的OAH。将邀请现有队列的参与者 间隔18-24个月的两次研究访视，每次访视将包括详细的神经认知功能 评估、身体功能测量、福尔斯和工具和日常生活活动，以及血液和 收集尿液样本进行分析，并建立生物储存库。总之，这些调查将 阐明cfmtDNA、免疫激活与OAH中老年相关综合征的关系。 这个项目提出了一个为期五年的多方面的培训计划下，博士指导马歇尔格莱斯比 作为主要导师，以及玛丽蔡博士，Lishomwa Ndhlovu和Eugenia Siegler作为共同导师。 他们将与一个科学咨询委员会一起，提供研究设计、生物标志物、 免疫学和老年科学，将允许支持这个项目的成功。的完成 拟议的项目将导致cfmtDNA作为老年综合征的生物标志物， OAH，以及一种转化研究工具，用于识别发病率和死亡率风险最高的OAH。后 完成此项目后，候选人将准备提交一份具有竞争力的R 03和R 01提案。