Role of Myeloid Cells in Cerebrovascular Permeability and Reactivity in Older HIV Infected Individuals

骨髓细胞在老年 HIV 感染者脑血管通透性和反应性中的作用

基本信息

批准号：
9343436
负责人：
SANJAY B. MAGGIRWAR
金额：
$ 71.58万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9343436
关键词：
Address Affect Age Aging Area Arteries Astrocytes Atherosclerosis Attention Blood Blood - brain barrier anatomy Blood Platelets Blood Vessels Blood capillaries Brain CD14 gene Cardiovascular Diseases Cardiovascular system Cell Adhesion Cell Adhesion Molecules Cerebral small vessel disease Cerebrovascular Circulation Cerebrovascular Disorders Cerebrum Chronic Complex Deposition Diagnosis Disease Endothelial Cells Evaluation Extravasation FCGR3B gene Frequencies Functional Magnetic Resonance Imaging Gender General Population HIV HIV Infections HMGB1 gene Image Imaging Techniques Immune Incidence Individual Infarction Infection Inflammatory Intercellular adhesion molecule 1 Investigation Iron Link Long-Term Effects Longitudinal Studies Measures Mediating Microcirculation Microglia Modeling Myeloid Cells Neopterin Older Population Pericytes Permeability Persons Phenotype Plasma Platelet Activation Platelet Factor 4 Play Population Predisposition Prevention strategy Process Property Proteins Rest Risk Risk Factors Role SIV Spin Labels Techniques Tissues Tumor necrosis factor receptor 11b Vascular Permeabilities Veins White Matter Hyperintensity activation product antiretroviral therapy arteriole base blood perfusion blood product brain abnormalities capillary central nervous system injury cerebral atrophy cerebral microbleeds cerebrovascular clinical Diagnosis clinical imaging cognitive performance cohort data modeling endothelial dysfunction imaging biomarker imaging modality immune activation lipoprotein-associated phospholipase A(2)monocyte neuroimaging neurovascular unit quantitative imaging therapeutic target white matter

项目摘要

HIV infected individuals, especially those older, are at increased risk of developing cerebrovascular disease (CBVD). While most of the recent investigations have focused on large vessel disease, cerebral small vessel disease (CSVD) has received much less attention despite its known role and long-term effect on cognitive performance and potentially more direct link to HIV-associated immune dysregulation. CSVD is diagnosed via neuroimaging. Typical findings include small subcortical infarcts, lacunes, white matter hyperintensity, enlarged perivascular spaces, cerebral microbleeds and brain atrophy. Quantitative MR techniques assess indirectly the altered microcirculation and blood brain barrier (BBB) by measuring vascular reactivity, cerebral blood flow, white matter microstructure and tissue susceptibility. Importantly, these quantitative imaging modalities can measure even subtle brain abnormalities that escape the evaluation by standard clinical imaging techniques. CSVD has been associated with markers secreted by myeloid cells. This is particularly relevant to HIV infected individuals. We and others have shown that the aberrant platelet activation during HIV/SIV infection causes an increase in platelet-monocyte complexes (PMCs) that drives monocyte maturation from CD14+/CD16- to the pro-inflammatory CD14(low)/CD16+ phenotype and that the reduced numbers of CD14+/CD16- monocytes are associated with pro-AS changes, BBB permeability and aging. Thus, PMCs could serve as markers and a therapeutic target of CSVD. Based on these observations, we hypothesize that PMCs, by affecting vascular permeability and reactivity, play a crucial role in mediating CSVD, especially in older HIV infected individuals. In a well characterize cohort for CBVD risk factors that includes an older-enriched HIV population (age≥50) and age matched uninfected individuals, we propose to address the following Specific Aims pertinent to CSVD in a 3-year longitudinal study. In Aim 1 we will assess whether changes in vascular reactivity (measured via rs-fMRI) and white matter microstructural integrity (measured via DTI) are associated with levels of PMCs. In Sub-Aim 1 we will determine whether areas with increased tissue susceptibility and decreased vascular reactivity are associated with decreased cerebral blood flow (CBF). In Aim 2 we will determine whether changes vascular reactivity and white matter microstructural integrity are associated with soluble products of pro-inflammatory monocytes (plasma levels of sCD163, neopterin, and HMGB1), platelet activation (platelet factor 4 [PF-4]) and with plasma markers of endothelial dysfunction (intercellular adhesion molecule 1 [sICAM- 1], vascular cellular adhesion molecule-1 [sVCAM-1], osteoprotegerin and lipoprotein-associated phospholipase A2 [Lp-PLA2] mass). In Sub-Aim 2 we will determine whether changes in brain iron deposition are associated with levels of PMCs, PF-4, plasma monocyte and endothelial soluble products. In Aim 3 we will model data generated from the previous aims in the context of cognitive performance.

艾滋病毒感染者，尤其是老年人，患脑血管疾病的风险增加（CBVD）虽然最近的大多数研究都集中在大血管疾病，但脑小血管疾病。尽管脑血管病 (CSVD) 的作用和对认知的长期影响是已知的，但它受到的关注却少得多。通过诊断 CSVD 的表现以及与 HIV 相关的免疫失调可能有更直接的联系。神经影像学检查的典型表现包括小的皮质下梗塞、腔隙、白质高信号、扩大。血管周围空间、脑微出血和脑萎缩技术可间接评估。通过测量血管反应性、脑血流量改变微循环和血脑屏障（BBB），重要的是，这些定量成像方式可以。甚至可以测量那些无法通过标准临床成像技术评估的细微大脑异常。脑小血管病与骨髓细胞分泌的标记物有关，这与艾滋病毒尤其相关。我们和其他人已经证明，HIV/SIV 感染期间血小板活化异常。导致血小板-单核细胞复合物 (PMC) 增加，从而驱动单核细胞成熟 CD14+/CD16- 转为促炎性 CD14(低)/CD16+ 表型，并且 CD14(低)/CD16+ 数量减少 CD14+/CD16- 单核细胞与 pro-AS 变化、BBB 通透性和衰老相关。可以作为 CSVD 的标志物和治疗靶点根据这些观察，我们发现了这一点。 PMCs 通过影响血管通透性和反应性，在介导 CSVD 中发挥着至关重要的作用，尤其是在老年艾滋病毒感染者。在一个明确的 CBVD 危险因素队列中，其中包括老年 HIV 人群（年龄≥50 岁）和年龄匹配的未感染者，我们建议解决以下与 CSVD 相关的具体目标在一项为期 3 年的纵向研究中，我们将评估血管反应性是否发生变化（通过测量）。 rs-fMRI）和白质微观结构完整性（通过 DTI 测量）与 PMC 水平相关。子目标 1 我们将确定组织敏感性增加和血管减少的区域是否在目标 2 中，我们将确定是否与脑血流量 (CBF) 减少有关。血管反应性和白质微结构完整性的变化与可溶性产物有关促炎单核细胞（sCD163、新蝶呤和 HMGB1 的血浆水平）、血小板活化（血小板因子 4 [PF-4]）和内皮功能障碍的血浆标志物（细胞间粘附分子 1 [sICAM- 1]、血管细胞粘附分子-1 [sVCAM-1]、骨保护素和脂蛋白相关磷脂酶 A2 [Lp-PLA2] 质量）在子目标 2 中，我们将确定脑铁沉积是否发生变化。与 PMC、PF-4、血浆单核细胞和内皮可溶性产物的水平相关。在目标 3 中，我们将在认知表现的背景下对先前目标生成的数据进行建模。