Effects of the neural and inflammatory response to stress on cerebrovascular risk in HIV infection

项目摘要 这是Felicia Chow博士的K23奖申请，她正在建立自己的研究者地位， 在艾滋病毒和脑血管疾病的交叉点进行以患者为导向的临床研究。K23奖将 为周博士提供必要的支持，以发展新的研究技能，并获得实用和 4个关键领域的概念性专业知识：1）脑和血管FDG-PET成像，2）机制和 心理压力的测量，3）观察数据的先进统计技术，以及4）设计， 临床试验的实施和分析。周博士组建了一个跨学科的导师团队（周博士）。 Priscilla Hsue是炎症和内皮功能障碍在血管内皮细胞损伤发病机制中作用的专家， Gil Rabinovici博士是使用多模式脑成像的专家， 大脑PET技术，以提高痴呆症的诊断; Elissa Epel博士，压力测量专家 及其对炎症和心脏代谢疾病的影响;弗雷德里克·赫克特博士，压力和 基于正念的艾滋病毒干预措施; Peter Bacchetti博士，统计方法分析专家 观察艾滋病毒数据），谁将指导她的研究和职业发展。这种多层次的指导 结构，嵌入在一个高度合作的培训环境，将是至关重要的，她的发展成为一个 独立研究者，最终目标是优化艾滋病毒感染者的脑血管健康。 随着艾滋病毒感染演变成一种慢性、可治疗的疾病，艾滋病毒感染者面临着几种额外的风险， 与艾滋病无关的并发症，包括中风。传统的血管风险因素（例如，高血压、吸烟） 仅占HIV患者脑血管风险的一部分。本提案将研究以下方面的作用： 心理压力，这是非常普遍的艾滋病毒感染者，在艾滋病毒相关的脑血管疾病的风险。博士 Chow假设，心理压力激活了促炎通路，导致炎症反应水平升高。 HIV感染者的脑血管风险她将利用NIH资助的两项研究的研究基础设施， 应激与神经炎症通路的关联（即，杏仁核活动免疫激活 炎性细胞因子）和脑血管风险标志物（即，颈动脉炎症 FDG-PET和脑血管反应性（经颅多普勒超声）在目标2中的横断面人群 艾滋病控制良好在目标3中，她将进行一项基于正念的减压对照试验 在一个子集的高压力的艾滋病毒感染者的干预，以获得初步了解的影响， 正念对神经炎症通路和脑血管风险标志物的影响。这项建议是一项 揭示心理压力对脑血管病风险的贡献的关键一步， 艾滋病毒和开发一个更大的随机对照试验，以严格测试减压的有效性 干预作为改善艾滋病毒感染者脑血管健康的一种预防性策略，这将是 R 01申请的重点是在授予期结束前准备和提交。

PROJECT SUMMARY This is an application for a K23 award for Dr. Felicia Chow, who is establishing herself as an investigator in patient-oriented clinical research at the intersection of HIV and cerebrovascular disease. This K23 award will provide Dr. Chow with the support necessary to develop new research skills and attain practical and conceptual expertise in 4 key areas: 1) brain and vascular FDG-PET imaging, 2) mechanisms and measurement of psychological stress, 3) advanced statistical techniques for observational data, and 4) design, conduct and analysis of clinical trials. Dr. Chow has assembled an interdisciplinary team of mentors (Dr. Priscilla Hsue, an expert in the role of inflammation and endothelial dysfunction in the pathogenesis of cardiovascular disease in HIV; Dr. Gil Rabinovici, an expert in use of multimodal brain imaging, including novel brain PET techniques, to improve diagnosis of dementia; Dr. Elissa Epel, an expert on measurement of stress and its effects on inflammation and cardiometabolic disease; Dr. Frederick Hecht, an expert on stress and mindfulness-based interventions in HIV; Dr. Peter Bacchetti, an expert on statistical approaches to analyzing observational HIV data), who will guide her research and career development. This multi-layered mentorship structure, embedded in a highly collaborative training environment, will be critical to her development into an independent investigator, with the ultimate goal of optimizing cerebrovascular health in people living with HIV. With the evolution of HIV infection into a chronic, treatable disease, people with HIV face excess risk of several non-AIDS-related complications, including stroke. Traditional vascular risk factors (e.g., hypertension, smoking) account for only a portion of excess cerebrovascular risk in HIV. This proposal will investigate the role of psychological stress, which is highly prevalent in people with HIV, in HIV-associated cerebrovascular risk. Dr. Chow hypothesizes that psychological stress activates pro-inflammatory pathways that contribute to elevated cerebrovascular risk in HIV. She will leverage the research infrastructure of two NIH-funded studies to evaluate the association of stress with the neural inflammatory pathway (i.e., amygdala activity, immune activation, inflammatory cytokines) in Aim 1 and with cerebrovascular risk markers (i.e., carotid arterial inflammation on FDG-PET and cerebral vasoreactivity by transcranial Doppler ultrasound) in Aim 2 in a cross-section of people with well-controlled HIV. In Aim 3, she will pilot a controlled trial of a mindfulness-based stress reduction intervention in a subset of high-stress individuals with HIV to gain preliminary insight into the impact of mindfulness on the neural inflammatory pathway and on cerebrovascular risk markers. This proposal is a crucial step toward uncovering the contribution of psychological stress to cerebrovascular risk in people with HIV and developing a larger randomized controlled trial to rigorously test the effectiveness of a stress reduction intervention as an adjunctive strategy to improving cerebrovascular health in people with HIV, which will be the focus of an R01 application to be prepared and submitted before the end of the award period.