Role of pannexin-1 hemichannels in NeuroAIDS

pannexin-1 半通道在 NeuroAIDS 中的作用

• 批准号: 9271671
• 负责人: Eliseo A Eugenin
• 金额: $ 72.01万
• 依托单位: RBHS-NEW JERSEY MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9271671
• 关键词: AIDS Dementia Complex; Address; Adverse effects; Animal Model; Binding; Biological Markers; Brain; CCR5 gene; CD4 Lymphocyte Count; CD4 Positive T Lymphocytes; CXCR4 gene; Cell Adhesion Molecules; Cells; Central Nervous System Diseases; Central Nervous System Infections; Cognition Disorders; Cytoplasm; Data; Disease; Electrophysiology (science); Ethnic Origin; Ethnic group; Extracellular Space; Functional disorder; Genetic Polymorphism; Goals; HIV; HIV Infections; HIV Receptors; HIV-1; Human; Image; Immune; Immune system; Impaired cognition; In Vitro; Individual; Infection; Infiltration; Inflammation; Inflammatory; Integration Host Factors; Ion Channel; Ischemia; Laboratories; Leukocytes; Life Cycle Stages; Link; Mediating; Modeling; Molecular; Monkeys; Nervous System Trauma; Neurologic; Pathogenesis; Pathogenicity; Pathologic; Pathology; Patients; Peripheral; Persons; Pharmacology; Phenotype; Physiological; Predisposition; Prostaglandins; Proteins; Purinoceptor; Regulation; Reperfusion Therapy; Reporting; Role; SIV; Sampling; Serum; Signaling Molecule; Stroke; Study models; Surface; Testing; Therapeutic Intervention; Time; Variant; Viral; Viral Load result; Virus Diseases; Virus Replication; base; channel blockers; chemokine; design; differential expression; experimental study; humanized mouse; in vivo; interdisciplinary approach; macrophage; monocyte; neuroAIDS; neuroinflammation; peptidomimetics; prevent; receptor; receptor expression; release factor; response; therapeutic target; trafficking

Project Abstract: According to WHO and UN reports, in 2014 an estimated 34 million persons worldwide were living with HIV. In addition to compromising the immune system, HIV can also infect the CNS early during the disease, leading to devastating neurological consequences (NeuroAIDS). A growing body of evidence indicates that neurological damage in NeuroAIDS is triggered not by the active viral replication but by the transmigration of HIV-infected leukocytes into the brain and the associated neuroinflammation. While it is well established that HIV uses host-encoded proteins to facilitate viral infection, replication and transmigration into the CNS, specific host factors involved in the pathogenesis of NeuroAIDS are still extremely poorly understood. Our laboratory recently identified pannexin-1 channels as essential components of the HIV life cycle in immune cells as well as in the pathogenesis of NeuroAIDS. In particular, we and others have demonstrated that pannexin-1 channel opening facilitates multiple steps of HIV-mediated CNS compromise, including: (1) regulation of CCR5 surface aggregation and trafficking in response to HIV infection; (2) HIV entry by direct regulation of the channel opening and subsequent release of intracellular ATP, auto-activating purinergic receptors; (3) release of intracellular factors such as ATP that promote inflammation; (4) monocyte differentiation and maturation in response to chemokines and/or HIV; (5) increased expression of several adhesion molecules required for leukocytes to transmigrate across the BBB; (6) neuroinflammation. We also found that ATP compromises BBB integrity and function, and our analysis of a large number of patient samples suggests that circulating ATP may be a biomarker of CNS disease. Our preliminary data indicate that different ethnic groups carry specific pannexin-1 polymorphisms and have differential expression and opening of this channel, potentially underlying, at least in part, the observed variation in susceptibility to HIV infection and NeuroAIDS among different ethnicities. Our recent preliminary data indicate that circulating ATP concentrations and their correlation with CNS compromise are also ethnicity related. Importantly, pannexin-1 channels have excellent potential as a therapeutic target because (1) their opening can be effectively blocked in vivo using several pannexin-1 channel blockers, including a specific mimetic peptide we recently designed; and (2) these channels mostly exist in a closed state under physiological conditions, minimizing potential side effects. This proposal is designed to define the mechanisms linking pannexin-1 channel opening to HIV receptor expression, trafficking, and function (Aim 1), leukocyte differentiation and transmigration into the CNS (Aim 2), and the role of neuroinflammatory factors released through the channel in BBB and CNS function (Aim 3). Finally, in Aim 4 we will examine the role of pannexin-1 channels in two animal models. Together, these experiments will reveal the role of an important new host factor in NeuroAIDS.

项目摘要： 根据世卫组织和联合国的报告，2014年，全球估计有3400万人与 艾滋病病毒。除了损害免疫系统外，HIV还可以在早期感染中枢神经系统 疾病，导致毁灭性神经系统后果（神经辅助）。越来越多的证据 表明神经辅导中的神经系统损害不是由主动病毒复制引起的，而是由 HIV感染的白细胞转移到大脑和相关的神经炎症中。虽然是 很好地确定，艾滋病毒使用宿主编码的蛋白质来促进病毒感染，复制和 转移到中枢神经系统中，神经辅助发病机理涉及的特定宿主因素仍然是 非常了解。我们的实验室最近将Pannexin-1通道确定为必不可少的 免疫细胞以及神经辅导的发病机理中HIV生命周期的成分。在 特别是，我们和其他人已经证明，pannexin-1频道的开放促进了多个步骤 HIV介导的中枢神经系统妥协，包括：（1）调节CCR5表面聚集和贩运 对HIV感染的反应； （2）通过直接调节通道开放和随后的直接调节HIV进入 释放细胞内ATP，自动激活嘌呤能受体； （3）释放细胞内因子 作为促进炎症的ATP； （4）响应趋化因子的单核细胞分化和成熟 和/或艾滋病毒； （5）白细胞所需的几个粘附分子表达增加 跨BBB移民； （6）神经炎症。我们还发现ATP损害了BBB的完整性 和功能，以及我们对大量患者样本的分析表明，循环ATP可能是 中枢神经系统疾病的生物标志物。我们的初步数据表明，不同的族裔有特定的 Pannexin-1多态性，具有差异表达和打开，可能 至少在某种程度上，基础观察到的观察到的艾滋病毒感染易感性和神经辅助的敏感性变化 不同的种族。我们最近的初步数据表明，循环ATP浓度及其 与中枢神经系统妥协的相关性也与种族有关。重要的是，pannexin-1通道具有 作为治疗靶标的巨大潜力，因为（1）它们的开口可以在体内有效阻止 使用几个Pannexin-1通道阻滞剂，包括我们最近设计的特定模拟肽； （2）这些通道主要存在于生理条件下的封闭状态，从而最大程度地降低潜力 副作用。该建议旨在定义将pannexin-1通道开放到 HIV受体表达，运输和功能（AIM 1），白细胞分化和移民到 中枢神经系统（AIM 2），以及通过BBB和 CNS功能（AIM 3）。最后，在AIM 4中，我们将研究Pannexin-1通道在两只动物中的作用 型号。这些实验将共同揭示重要的新宿主因子在神经辅助中的作用。