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

项目总结 这是一份K23奖项的申请书，给FIXIA CHOW博士，她正在成为一名研究员 以患者为中心的HIV和脑血管疾病交叉点的临床研究。这个K23奖项将 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)观察数据的高级统计技术，4)设计， 进行和分析临床试验。周博士组建了一个跨学科的导师团队(Dr。 Priscilla Hsue，研究炎症和内皮功能障碍在糖尿病发病机制中的作用的专家 艾滋病毒中的心血管疾病；吉尔·拉比诺维奇博士，多模式脑成像的专家，包括 脑PET技术，提高痴呆症的诊断；埃丽莎·埃佩尔博士，压力测量专家 以及它对炎症和心脏代谢性疾病的影响；弗雷德里克·赫克特博士，研究压力和心脏代谢疾病的专家 以正念为基础的艾滋病毒干预；彼得·巴切蒂博士，分析统计方法的专家 她将指导她的研究和职业发展。这种多层次的导师关系 结构，嵌入一个高度协作的培训环境，将是她发展成为一名 独立调查者，最终目标是优化艾滋病毒携带者的脑血管健康。 随着艾滋病毒感染演变为一种慢性、可治疗的疾病，艾滋病毒携带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。传统的血管危险因素(如高血压、吸烟) 仅占艾滋病毒超额脑血管风险的一部分。这项提案将调查 心理应激在艾滋病毒携带者中非常普遍，与艾滋病毒相关的脑血管风险有关。Dr。 Chow假设，心理压力会激活促炎途径，从而导致 艾滋病毒中的脑血管风险。她将利用NIH资助的两项研究的研究基础设施来评估 应激与神经炎性通路(即杏仁核活动、免疫激活、 炎性细胞因子)与脑血管危险标记物(即颈动脉炎症 横断面人群AIM 2的FDG-PET和经颅多普勒超声脑血管反应性 艾滋病病毒控制得很好。在目标3中，她将进行一项基于正念的压力减轻的对照试验 对部分艾滋病毒高应激个体进行干预以初步了解 专注于神经炎症途径和脑血管风险标记物。这项建议是一项 在揭示心理应激对脑血管疾病风险的贡献方面迈出了关键的一步 并开发了一项更大规模的随机对照试验，以严格测试减压的有效性 将干预作为改善艾滋病毒感染者脑血管健康的辅助策略，这将是 在授权期结束前准备和提交的R01申请的重点。

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.