Blood brain barrier injury in HIV infection complicated by diabetes: Mechanisms and protective strategies preventing cognitive impairment

HIV感染并发糖尿病的血脑屏障损伤：预防认知障碍的机制和保护策略

基本信息

批准号：
10400911
负责人：
Yuri Persidsky
金额：
$ 50.25万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2024-04-30
项目状态：
已结题

项目摘要

Despite combined antiretroviral therapy (ART) achieving efficient HIV replication control, HIV- associated neurocognitive disorders (HAND) continue to be highly prevalent in HIV-infected patients. One of the explanations could be constant compromise of blood brain barrier (BBB) driven by chronic inflammatory responses documented in HIV-infected individuals even with well-controlled virus replication yet with HAND progression. Chronic neuroimmune activation is present in ART-treated patients as indicated by elevated levels of soluble inflammatory factors in the cerebrospinal fluid and blood. Diabetes mellitus (DM) is a well-known comorbidity of HAND in HIV-infected patients. BBB dysfunction has been linked recently to dementia development, specifically in DM patients. BBB injury has been documented in animal models of diabetes showing memory deficits and was associated with dysfunction of brain pericytes supporting endothelial cells. Taking together clinical and experimental data, BBB injury exists both in HIV and DM, likely contributing to cognitive decline. However, its extent, exact cellular targets and mechanisms are largely unknown. We propose that cognitive impairment in HIV- infected individuals is mediated by BBB injury that is further aggravated by metabolic alterations associated with DM causing HAND. Preliminary data support this idea showing elevated glucose levels correlated with increased BBB permeability, cognitive impairment, microglia activation and loss of pericytes in animal models for DM types 1 and 2. We found a decrease in pericyte coverage and expression of tight junction proteins in human brain tissues from HIV patients with DM and evidence of HAND. Using our in vitro BBB models, we demonstrated diminution of barrier integrity, enhanced monocyte adhesion, changes in cytoskeleton and overexpression of adhesion molecules after exposure to HIV and DM-relevant stimuli. We hypothesize that prevention of BBB compromise in DM/HIV will diminish neurocognitive decline independently of tight glucose control. We will identify biomarkers of such BBB injury, correlate with barrier damage and cognitive decline, define signaling pathways associated with BBB injury in DM/HIV and test novel treatment approaches. We will study the contribution of DM- and HIV- mimicking conditions on cognition and BBB injury in cross-validating experiments using well- established in vitro systems (co-culture of human primary brain microvascular endothelial cells/primary human brain pericytes), functional assays, animal models of DM types 1 and 2 combined with HIV brain exposure and `humanized' NSG mice with chronic HIV infection and diabetes. Results of such studies will open opportunities for very much needed individualized treatment for HAND.

尽管联合抗逆转录病毒疗法（ART）实现了有效的 HIV 复制控制，但 HIV- 相关神经认知障碍 (HAND) 在 HIV 感染者中仍然非常普遍患者。原因之一可能是血脑屏障（BBB）的不断受损由 HIV 感染者记录的慢性炎症反应驱动，即使病毒复制得到良好控制，但仍具有 HAND 进展。慢性神经免疫激活是存在于接受 ART 治疗的患者中，表现为可溶性炎症因子水平升高存在于脑脊液和血液中。糖尿病（DM）是一种众所周知的合并症 HIV感染者的手。最近发现血脑屏障功能障碍与痴呆症有关的发展，特别是在糖尿病患者中。动物模型中已记录了血脑屏障损伤糖尿病表现出记忆缺陷并与大脑周细胞功能障碍有关支持内皮细胞。综合临床和实验数据，血脑屏障损伤存在在艾滋病毒和糖尿病中，都可能导致认知能力下降。然而，它的范围，确切的细胞目标和机制在很大程度上是未知的。我们认为 HIV 患者的认知障碍受感染的个体是由血脑屏障损伤介导的，代谢改变进一步加剧了血脑屏障损伤与导致手部疾病的 DM 相关。初步数据支持这一观点，表明血糖水平与血脑屏障通透性增加、认知障碍、小胶质细胞相关 1 型和 2 型 DM 动物模型中周细胞的激活和损失。我们发现 HIV 人脑组织中周细胞的覆盖和紧密连接蛋白的表达患有 DM 和 HAND 证据的患者。使用我们的体外 BBB 模型，我们证明了屏障完整性降低、单核细胞粘附增强、细胞骨架发生变化暴露于 HIV 和 DM 相关刺激后粘附分子过度表达。我们假设预防 DM/HIV 患者的 BBB 受损将减少神经认知衰退独立于严格的血糖控制。我们将识别此类 BBB 损伤的生物标志物，并将其与随着屏障损伤和认知能力下降，定义与 BBB 损伤相关的信号通路糖尿病/艾滋病毒并测试新的治疗方法。我们将研究 DM 和 HIV 的贡献使用良好的交叉验证实验来模拟认知和 BBB 损伤的条件建立体外系统（人原代脑微血管内皮细胞共培养）细胞/原代人脑周细胞）、功能测定、1 型和 2 型 DM 动物模型结合 HIV 大脑暴露和慢性 HIV 感染的“人源化”NSG 小鼠，糖尿病。此类研究的结果将为非常需要的个性化提供机会手部治疗。