Aging with HIV: Novel Biomarkers of Inflammation and Morbidity

项目摘要/摘要 候选人的职业目标是成为一名研究艾滋病毒和衰老的独立内科科学家， 艾滋病毒(OAH)老年患者的医疗合并症和老年综合征的负担增加。这个 候选人通过获得治疗OAH的临床专业知识为实现这一目标奠定了基础， 从事研究，并获得临床和翻译研究硕士学位。要实现 她的职业目标，候选人将需要扩大她的老年科学和翻译研究技能， 包括本次重新提交报告中所述的其他生物统计和研究方法培训。 候选人培训的一个关键部分将是开展拟议的研究项目。尽管 有效的抗逆转录病毒药物，OAH承担着更大的医疗合并症和老年病负担 与艾滋病毒阴性的同龄人相比，他们有更多的症状。研究炎症提供的生物标志物的翻译研究 作为洞察OAH观察到的加速/加剧衰老过程的机会。无细胞 线粒体dna(Cfmtdna)是由应激和坏死下垂引起的细胞死亡释放出来的。 并有可能作为慢性免疫激活和调节失调的中介和标志物。 我们假设cfmtDNA将与较低的认知表现和更大的脆弱性有关 OAH的纵向研究。此前，我们在我们机构研究了一群OAH(55岁及以上)， 那些有认知障碍的人比没有认知障碍的人血浆中cfmtDNA的平均水平更高 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的认知之间的关联；2)确定两者之间的关联 CfmtDNA与OAH的纵向身体功能；3)评估其免疫刺激潜能。 伴有和不伴有认知功能减退的OAH患者的cfmtDNA。我们现有队列中的参与者将被邀请 回来进行两次相隔18-24个月的研究访问，每次访问将包括详细的神经认知 评估、身体机能测量、跌倒、器质性和日常生活活动，以及血液和 收集尿样用于分析和创建生物储存库。总而言之，这些调查将使 CfmtDNA、免疫激活与OAH老年相关综合征关系的研究 该项目提出了一个由马歇尔·格拉斯比博士指导的为期五年、多方面的培训计划。 作为主要导师，以及Mary Choi博士、Lishomwa Ndhlovu博士和Eugenia Siegler博士作为联合导师。 他们将与科学咨询委员会一起，提供研究设计、生物标记物、 免疫学和老年学将支持这一项目的成功。该计划的完成 拟议的项目将加强对cfmtDNA作为老年综合征生物标记物的了解 OAH，以及确定OAH发病率和死亡率最高风险的转换研究工具。之后 完成这个项目，候选人将准备提交一份具有竞争力的R03和R01提案。

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.