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（HAND）在HIV感染者中仍然非常普遍。 患者其原因之一可能是血脑屏障（BBB）持续受损 在HIV感染者中记录的慢性炎症反应驱动下， 病毒复制得到良好控制，但伴有HAND进展。慢性神经免疫激活是 存在于ART治疗患者中，如可溶性炎症因子水平升高所示 在脑脊液和血液中。糖尿病（DM）是一种众所周知的合并症， HIV感染者的手。BBB功能障碍最近与痴呆症有关 尤其是在糖尿病患者中。BBB损伤已在以下动物模型中记录： 糖尿病表现出记忆缺陷，并与脑周细胞功能障碍有关 支持内皮细胞。结合临床和实验数据，存在BBB损伤， 在艾滋病和糖尿病中，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。我们认为艾滋病患者的认知障碍- 受感染的个体通过代谢改变进一步加重的BBB损伤介导 与糖尿病相关的手。初步数据支持这一观点， 葡萄糖水平与BBB通透性增加、认知障碍、小胶质细胞 1型和2型DM动物模型中周细胞的活化和损失。我们发现 HIV感染者脑组织中周细胞覆盖率和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，细胞骨架变化， 暴露于HIV和DM相关刺激后粘附分子的过度表达。我们 假设在DM/HIV中预防BBB损害将减少神经认知下降 独立于严格的葡萄糖控制。我们将鉴定这种BBB损伤的生物标志物， 与屏障损伤和认知能力下降，定义与BBB损伤相关的信号通路 并测试新的治疗方法。我们将研究糖尿病和艾滋病的贡献， 在交叉验证实验中模拟认知和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的动物模型 结合HIV脑暴露和慢性HIV感染的“人源化”NSG小鼠， 糖尿病这些研究的结果将为非常需要的个性化提供机会。 手的治疗。