Vascular contributions to HIV-associated Neurocognitive Disorders (HAND)

血管对 HIV 相关神经认知障碍 (HAND) 的影响

基本信息

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
项目类别：
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&apos 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

项目摘要

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：作为患有艾滋病毒（PWH）年龄的人，慢性合并症，例如脑血管疾病和认知较差变得更加普遍。脑血管疾病和痴呆症发生差异 PWH。可能的因素可能包括不成比例的血管风险因素的流行率，例如 PWH中的高血压，糖尿病，血脂异常和吸烟。此外，PWH的社会经济背景（其中包括但不限于同性恋恐惧症，结构性种族主义和社会污名）可能会翻译成压力源这可能导致血管健康较差。在此提案中，我们试图填补有关如何的知识差距血管危险因素和社会经济压力源可能影响PWH中的脑血管疾病和认知。我们提出内皮激活的固体血液生物标志物，例如血管细胞粘附分子-1 （VCAM-1），细胞间粘合分子-1（ICAM-1）和肿瘤坏死因子α（TNFα）是关键这些关系的介体，更重要的是，它们可能是治疗靶标。在AIM 1中，我们假设不受控制的血管危险因素和社会经济压力源与HIV相互作用与年龄，性别匹配的年龄，性别相比，内皮激活的血液生物标志物水平增加未感染的控件。在AIM 2中，我们提出与HIV相关脑血管疾病中的分布相比未感染的对照是由内皮激活的血液生物标志物水平升高介导的。在AIM 3中，我们假设基于MRI基于MRI的神经变性和PWH中的分布与匹配相比未感染的对照是由内皮激活和MRI-的血液生物标志物水平升高介导的基于脑血管疾病。确认内皮激活剂对其他炎症的中心作用分子，我们将使用包括套索不相互作用的五个模型进行确认分析术语，具有相互作用项的套索，RF，XGBoost和模型平均值。通过执行这些目标，我们将产生严格的科学证据，以支持HIV相关脑血管的独特生理病理学疾病和神经退化基因甲基。此外，通过建立内皮激活作为关键途径介导HIV相关的脑血管疾病和神经退行性差异，我们将提供初步支持以测试修改这些炎症途径（例如TNFα封锁）是否可能在本研究中证明对PWH或某些亚组有益。