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

• 批准号: 10160956
• 负责人: Yuri Persidsky
• 金额: $ 50.82万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10160956
• 关键词: Adhesions; Advanced Glycosylation End Products; Affect; Animal Model; Attenuated; Behavior; Behavior assessment; Biological Assay; Biological Markers; Blood; Blood - brain barrier anatomy; Blood Glucose; Blood-Retinal Barrier; Brain; Brain Injuries; Cell Adhesion Molecules; Cells; Cerebrospinal Fluid; Cerebrum; Chronic; Clinical; Coculture Techniques; Cognition; Cognitive deficits; Coupled; Cytoskeleton; Data; Dementia; Development; Diabetes Mellitus; Diabetic Retinopathy; Endothelial Cells; Endothelium; Exposure to; Functional disorder; Gene Expression; Genes; Glucose; HIV; HIV Envelope Protein gp120; HIV Infections; HIV-associated neurocognitive disorder; Hippocampus (Brain); Human; Human immunodeficiency virus test; Hyperglycemia; Image; Immune response; Impaired cognition; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Infusion procedures; Injury; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Leukocytes; Link; Mediating; Memory impairment; Metabolic; Microglia; Microvascular Dysfunction; Modeling; Mus; Neuraxis; Neurocognitive Deficit; Neuroimmune; Neuronal Dysfunction; Obesity; Patients; Pattern; Pericytes; Permeability; Phenotype; Poison; Poly(ADP-ribose) Polymerases; Prevention; Proteins; Risk Factors; Signal Pathway; Stimulus; Structure; Supporting Cell; System; Testing; Therapeutic Intervention; Tight Junctions; Tissues; Up-Regulation; Virus; Virus Replication; Work; antiretroviral therapy; base; blood glucose regulation; blood-brain barrier disruption; blood-brain barrier function; blood-brain barrier permeabilization; brain dysfunction; brain endothelial cell; brain tissue; cellular targeting; cerebrovascular; comorbidity; diabetic; diabetic patient; experimental study; glucose metabolism; humanized mouse; imaging study; in vitro Model; in vivo; individualized medicine; macrovascular disease; migration; mild cognitive impairment; monocyte; neuroinflammation; novel; overexpression; prevent; response; white matter

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)实现了有效的艾滋病毒复制控制，但艾滋病毒- 相关的神经认知障碍(手)在艾滋病毒感染者中仍然非常普遍 病人。其中一个解释可能是血脑屏障(BBB)的持续损害。 由HIV感染者记录的慢性炎症反应驱动，即使是 病毒复制得到了很好的控制，但仍有进展。慢性神经免疫激活是 在接受抗逆转录病毒治疗的患者中存在，表现为可溶性炎症因子水平升高 在脑脊液和血液中。糖尿病(DM)是一种众所周知的 上交艾滋病病毒感染者。血脑屏障功能障碍最近被认为与痴呆症有关 发展，特别是在糖尿病患者中。血脑屏障损伤已经在动物模型中被记录下来 糖尿病表现为记忆缺陷，并与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，血脑屏障损伤是存在的 在艾滋病毒和糖尿病中都是如此，可能会导致认知能力下降。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-- 感染者由血脑屏障损伤介导，代谢改变进一步加剧了这种损伤 与糖尿病引起的手有关。初步数据支持这一观点，显示出 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 在1型和2型糖尿病动物模型中周细胞的激活和丢失。我们发现 HIV感染人脑组织中周细胞覆盖率及紧密连接蛋白的表达 糖尿病患者和手的证据。使用我们的体外血脑屏障模型，我们展示了 屏障完整性降低，单核细胞黏附增强，细胞骨架改变和 暴露于HIV和DM相关刺激后黏附分子的过度表达。我们 假设预防糖尿病/艾滋病患者的血脑屏障损害将减少神经认知能力的下降 与严格的血糖控制无关。我们将确定这种血脑屏障损伤的生物标记物，相关 对于屏障损伤和认知功能下降，定义与血脑屏障损伤相关的信号通路 在糖尿病/艾滋病毒方面，并测试新的治疗方法。我们将研究糖尿病和艾滋病毒的贡献- 用Well-Well模拟交叉验证实验中认知和血脑屏障损伤的条件 建立体外培养体系(共培养人原代脑微血管内皮细胞 细胞/原代人脑周细胞)、功能分析、1型和2型糖尿病动物模型 与HIV脑暴露和慢性HIV感染的人源化NSG小鼠相结合 糖尿病。这些研究的结果将为非常需要的个性化提供机会 手部的治疗。