Vascular contributions to HIV-associated Neurocognitive Disorders (HAND)

血管对 HIV 相关神经认知障碍 (HAND) 的影响

• 批准号: 10405357
• 负责人: Jose Gutierrez
• 金额: $ 82.19万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10405357
• 关键词: Affect; Age; Aging; Alzheimer' s Disease; Amyloid deposition; Anti-Inflammatory Agents; Anti-Retroviral Agents; Biological; Biological Markers; Blood; Blood Vessels; Cerebrovascular Disorders; Chronic; Chronic Disease; Clinical; Cognition; Data; Dementia; Diabetes Mellitus; Disease; Dyslipidemias; Elderly; Endothelium; Equipoise; Ethnic Origin; Functional disorder; Future; HIV; HIV Seronegativity; HIV-associated neurocognitive disorder; Health; Homophobia; Hypertension; Impaired cognition; Individual; Infection; Inflammation; Inflammatory; Injury; Intercellular adhesion molecule 1; Knowledge; Lasso; Life Expectancy; Magnetic Resonance Imaging; Measures; Mediating; Mediation; Mediator of activation protein; Modeling; Modification; Morbidity - disease rate; Nerve Degeneration; Pathway interactions; Persons; Plasma; Play; Population; Prevalence; Process; Production; Quality of life; Residual state; Risk; Role; Smoking; Stroke; Structural Racism; Subgroup; TNF gene; Testing; Therapeutic; Therapeutic Intervention; Translating; Vascular Cell Adhesion Molecule-1; Vascular Diseases; aging population; antiretroviral therapy; base; cohort; comorbidity; cytokine; dementia risk; disease disparity; disparity reduction; intercellular cell adhesion molecule; sex; social stigma; socioeconomics; stressor; synergism; tau phosphorylation; therapeutic target; vascular contributions; vascular risk factor

PROJECT SUMMARY/ABSTRACT: As people with HIV (PWH) age, chronic comorbidities such as cerebrovascular disease and poorer cognition become more prevalent. There exist a disparity in the rates of cerebrovascular disease and dementia among PWH. Possible contributing factors include disproportionate prevalence of vascular risk factors such as hypertension, diabetes, dyslipidemia and smoking in PWH. Additionally, the socioeconomic context of PWH (that includes but is not limited to homophobia, structural racism and societal stigma) may translate in stressors that may contribute to poorer vascular health. In this proposal, we attempt to fill in the knowledge gap of how vascular risk factors and socioeconomic stressors may affect cerebrovascular disease and cognition in PWH. We propose that soluble blood biomarkers of endothelial activation such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and tumor necrosis factor alpha (TNFα), are key mediators of these relationships, and more importantly, they could be therapeutic targets. In aim 1, we hypothesize that uncontrolled vascular risk factors and socioeconomic stressors interact with HIV to relate to increased levels of blood biomarkers of endothelial activation compared to age-, sex-, and ethnicity-matched uninfected controls. In aim 2, we propose that disparities in HIV-related cerebrovascular disease compared to uninfected controls are mediated by increased levels of blood biomarkers of endothelial activation. In aim 3, we hypothesize that disparities in MRI-based neurodegeneration and cognition in PWH compared to matched uninfected controls are mediated by increased levels of blood biomarkers of endothelial activation and MRI- based cerebrovascular disease. To confirm the central role of endothelial activators over other inflammatory molecules, we will carry out confirmatory analyses using five models that include LASSO without interaction terms, Lasso with interaction terms, RF, XGBoost and Model Average. With the execution of these aims, we will produce rigorous scientific evidence supporting the unique physiopathology of HIV-related cerebrovascular disease and neurodegeneracion. Furthermore, by establishing endothelial activation as a key pathway in mediating HIV-related disparities in cerebrovascular disease and neurodegeneration, we will provide preliminary support to test whether modification of these inflammatory pathways (e.g. TNFα blockade) may prove beneficial in PWH or in certain subgroups to be identified in this study.

项目摘要/摘要： 随着HIV感染者(PWH)年龄的增长，脑血管疾病等慢性并存疾病和认知功能较差 变得更加普遍。脑血管疾病和痴呆症的发病率存在差异。 威尔斯亲王医院。可能的致病因素包括血管风险因素不成比例的流行，如 高血压、糖尿病、血脂异常和吸烟与PWH相关。此外，威尔斯亲王医院的社会经济背景 (这包括但不限于同性恋恐惧症、结构性种族主义和社会耻辱)可能会转化为压力源 这可能会导致血管健康状况变差。在这项提议中，我们试图填补关于如何 血管危险因素和社会经济应激源可能影响PWH患者的脑血管疾病和认知功能。 我们认为血管细胞黏附分子-1等血管内皮细胞活化的可溶性血液生物标志物 血管细胞黏附分子-1、细胞间黏附分子-1和肿瘤坏死因子-α(肿瘤坏死因子α)是关键 这些关系的调解人，更重要的是，他们可能是治疗的目标。在目标1中，我们 假设未控制的血管危险因素和社会经济应激源与艾滋病毒相互作用 与年龄、性别和种族匹配的血管内皮细胞激活的血液生物标记物水平相比 未感染的对照组。在目标2中，我们提出艾滋病毒相关脑血管疾病的差异与 未感染的对照组是通过内皮激活的血液生物标志物水平增加而调节的。在目标3中，我们 假设PWH患者与配对患者相比在基于MRI的神经退行性变和认知方面的差异 未感染对照组的血管内皮细胞活化和核磁共振成像生物标志物水平升高。 以脑血管疾病为基础。确认内皮细胞激活剂相对于其他炎症性物质的核心作用 分子，我们将使用五个模型进行验证性分析，其中包括无相互作用的套索 术语、带有相互作用术语的套索、RF、XGBoost和模型平均值。随着这些目标的实现，我们 将提供严格的科学证据支持艾滋病毒相关脑血管的独特生理病理 疾病和神经退行性变。此外，通过将内皮细胞激活建立为 在脑血管疾病和神经退行性变中调解艾滋病毒相关的差异，我们将提供 初步支持测试修改这些炎症途径(例如，阻断肿瘤坏死因子α)是否可能 证明对PWH或本研究中确定的某些亚组有益。