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.

尽管结合了抗逆转录病毒疗法（ART），可实现有效的HIV复制控制，HIV- 相关的神经认知障碍（手）在HIV感染中仍然非常普遍 患者。一种解释之一可能是血脑屏障（BBB）的持续妥协 受艾滋病毒感染者记录的慢性炎症反应的驱动 控制的病毒复制良好，但手动进展。慢性神经免疫性激活是 如可溶性炎症因子水平升高所示，在经过艺术治疗的患者中存在 在脑脊液和血液中。糖尿病（DM）是众所周知的合并症 手中感染了艾滋病毒的患者。 BBB功能障碍最近与痴呆症有关 发育，特别是在DM患者中。在动物模型中已记录了BBB损伤 糖尿病显示记忆缺陷，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，BBB损伤存在 在艾滋病毒和DM中，都可能导致认知能力下降。但是，它的范围是精确的细胞 目标和机制在很大程度上未知。我们建议在艾滋病毒中认知障碍 受感染的个体是由BBB损伤介导的，BBB损伤进一步加剧了代谢改变 与DM引起手相关。初步数据支持这个想法，显示 葡萄糖水平与BBB渗透性增加，认知障碍，小胶质细胞相关 DM类型1和2的动物模型中的激活和周细胞的丧失。我们发现有所减少 HIV的人脑组织中紧密连接蛋白的周细胞覆盖率和表达 DM和手证据的患者。使用我们的体外BBB模型，我们证明了 屏障完整性的降低，单核细胞粘附增强，细胞骨架的变化和 暴露于HIV和与DM相关的刺激后的粘附分子过表达。我们 假设预防DM/HIV中BBB妥协会减少神经认知能力下降 独立于紧密的葡萄糖控制。我们将确定这种BBB损伤的生物标志物，相关 随着障碍损伤和认知能力下降，定义与BBB损伤相关的信号通路 在DM/HIV和测试新型治疗方法中。我们将研究DM-和HIV-的贡献 模仿对跨验性实验中认知和BBB损伤的条件 建立的体外系统（人类原发性脑微血管内皮的共同培养 细胞/原发性人脑周细胞），功能测定，DM类型1和2的动物模型 与HIV脑暴露和具有慢性HIV感染的“人源化” NSG小鼠结合 糖尿病。此类研究的结果将为非常需要的个性化开放机会 手的治疗。