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

• 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
• 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

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，特别是老年人，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CSVD对认知功能的作用和长期影响是已知的，但它受到的关注要少得多。 性能和潜在的更直接的联系，艾滋病毒相关的免疫失调。CSVD通过以下方式诊断： 神经成像典型的表现包括小的皮质下梗死、腔隙、白色高信号、增大 血管周围间隙、脑微出血和脑萎缩。定量磁共振技术间接评估 通过测量血管反应性，脑血流量， 白色物质显微结构和组织磁化率。重要的是，这些定量成像方式可以 即使是无法通过标准临床成像技术进行评估的细微脑部异常也能测量出来。 CSVD与髓样细胞分泌的标志物相关。这一点与艾滋病毒特别相关 感染的人。我们和其他人已经表明，在HIV/SIV感染过程中异常的血小板活化， 导致血小板-单核细胞复合物（PMC）增加， CD 14 +/CD 16-转化为促炎性CD 14（低）/CD 16+表型， CD 14 +/CD 16-单核细胞与前AS变化、BBB通透性和衰老相关。因此，PMC 可作为CSVD的标志物和治疗靶点。基于这些观察，我们假设， PMCs通过影响血管通透性和反应性，在介导CSVD中起关键作用，特别是在 老年艾滋病毒感染者。 在一个充分表征CBVD风险因素的队列中，其中包括老年HIV人群（年龄≥50岁） 和年龄匹配的未感染个体，我们建议解决以下与CSVD相关的具体目标 在一项为期三年的纵向研究中。在目标1中，我们将评估血管反应性的变化（通过 rs-fMRI）和白色物质微结构完整性（通过DTI测量）与PMC水平相关。在 子目标1，我们将确定组织敏感性增加和血管敏感性降低的区域 反应性与脑血流量（CBF）减少有关。在目标2中，我们将确定 血管反应性和白色物质显微结构完整性的变化与可溶性 促炎性单核细胞（sCD 163、新蝶呤和HMGB 1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]）。 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-PLA 2]质量）。在子目标2中，我们将确定脑铁沉积的变化是否 与PMCs、PF-4、血浆单核细胞和内皮可溶性产物水平相关。 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。