HIV and substances of abuse influence exosomes and endothelial cell function

HIV 和滥用物质影响外泌体和内皮细胞功能

• 批准号: 8987274
• 负责人: Dirk P Dittmer
• 金额: $ 39.2万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8987274
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Acute; Address; Affect; Animal Model; Animals; Behavioral; Behavioral Sciences; Biogenesis; Biological; Biological Assay; Biological Markers; Biology; Blood; Blood - brain barrier anatomy; Blood Circulation; Blood Vessels; Brain; Cancer Patient; Cannabinoids; Cell Line; Cell physiology; Cells; Cellular biology; Clinical; Clinical Sciences; Cocaine; Data; Development; Disease; Disease Progression; Distant; Drug usage; Endothelial Cells; Environment; Exposure to; Extravasation; Functional disorder; HIV; HIV Infections; HIV risk; Human; Inflammatory; Intervention; Knowledge; Lead; Leukocytes; Liposomes; Liquid substance; Lymphatic; Lymphatic Endothelial Cells; Malignant Neoplasms; Mediator of activation protein; Methods; MicroRNAs; Mus; Neurologic; Neurologic Manifestations; Neuropathogenesis; Organ; Pathogenesis; Patients; Permeability; Pharmaceutical Preparations; Pharmacology; Phenotype; Plasma; Process; Production; Proteins; Research; Research Personnel; Residual Tumors; Residual state; Risk; Role; Signal Transduction; Site; Source; Staging; Structure; Substance abuse problem; Substance of Abuse; System; Testing; Tight Junctions; Vesicle; Viral Pathogenesis; Viral Proteins; Work; biobank; cell behavior; cell growth; cell type; cofactor; cytokine; drug of abuse; experience; extracellular; in vivo; in vivo Model; innovation; insight; intercellular communication; mouse model; nervous system disorder; novel; pathogen; public health relevance; response; therapeutic target; tool; uptake

 DESCRIPTION (provided by applicant): HIV infection results in CNS complications, with nearly 75% of patients with advanced HIV disease showing subclinical to clinical neurological manifestations. Additional sequelae have patients on long-term successful cART therapy who suffer from residual and end organ diseases of HIV infection. Endothelial cell dysfunction is central to HIV neuropathogenesis. A compromised blood brain barrier results in increased leukocyte transmigration, HIV infection, and the establishment of a highly inflammatory environment, which further aggravates HIV-associated neurological disease. Microvesicles are secreted from nearly every cell type. Many types exist, which we shall refer to collectively as exosomes. These circulate in the bloodstream of HIV patients. They influence intercellular communication at both local and distant sites from their cellular source. Vascular, lymphatic, and barrier endothelial cells, perhaps more than any other cell type, are constantly exposed to circulating exosomes. HIV infection can affect the composition of exosomes and utilizes these vesicles to facilitate viral pathogenesis and spread. Exosomes from infected cells can contain viral proteins, host microRNAs and proteins that trigger responses in endothelial cells, all of which can promote HIV pathogenesis. We showed this for exosomes circulating in HIV associated cancer patients and animal models (Chugh et al. PLoS Pathog. 2013;9(7):e1003484). Drugs of abuse including cocaine and cannibinoids are associated with increased HIV risk and these substances can be detrimental to HIV progression and contribute to HIV-associated neurological complications. Several studies have demonstrated that these drugs independently trigger distinct changes in endothelial cell function. However, the influence of drugs of abuse on exosome production, composition and function, especially in the context of HIV infection, represents a significant gap in our knowledge. Therefore, there is a critical need to understand the role of exosomes in HIV pathogenesis and factors that may influence HIV exosome-induced intercellular communication such as drug use. This may also lead to identification of potential therapeutic targets to block specific exosomal cargo and/or downstream effects in endothelial cells that may promote disease progression. This R01 application seeks to address how exosomes from HIV-infected cells affect blood brain barrier permeability and endothelial cell dysfunction and how drugs of abuse may influence exosomal cargo and function.

 描述（由适用提供）：HIV感染导致中枢神经系统并发症，近75％的晚期HIV疾病患者表现为临床神经系统表现。额外的后遗症患有长期成功的手推车治疗患者，患有艾滋病毒感染的残留和最终器官疾病。内皮细胞功能障碍是HIV神经病发生的核心。受损的血脑屏障导致白细胞传播，艾滋病毒感染和建立高度炎症环境，这进一步加剧了与HIV相关的神经系统疾病。微泡来自几乎每种细胞类型。存在许多类型，我们将其集体称为外泌体。这些在艾滋病毒患者的血液中循环。它们会影响来自细胞来源的局部和遥远位点的细胞间通信。血管，淋巴和屏障内皮细胞，可能比任何其他细胞类型都多，经常暴露于循环外泌体。 HIV感染会影响外泌体的组成，并利用这些蔬菜促进病毒发病机理和扩散。受感染细胞的外泌体可能包含病毒蛋白，宿主microRNA和蛋白质，这些蛋白会触发内皮细胞中的反应，所有这些都可以促进HIV发病机理。我们证明了这一点是针对艾滋病毒相关癌症患者和动物模型循环的外泌体（Chugh等人，PLOS病原体。2013; 9（7）：E1003484）。包括可卡因和小食虫类药物在内的滥用药物与HIV风险增加有关，这些物质可以确定为HIV进展，并导致与HIV相关的神经系统并发症。几项研究表明，这些药物独立触发了内皮细胞功能的明显变化。但是，滥用药物对外泌体产生，组成和功能的影响，尤其是在艾滋病毒感染的背景下，这在我们的知识上是一个很大的差距。因此，迫切需要了解外泌体在HIV发病机理中的作用以及可能影响HIV外生体诱导的细胞间交流（例如药物使用）的因素。这也可能导致鉴定潜在的治疗靶标，以阻止内皮细胞中特定的外部货物和/或下游效应，以促进疾病进展。该R01应用程序旨在解决来自HIV感染细胞的外泌体如何影响血脑屏障的通透性和内皮细胞功能障碍以及滥用药物如何影响外泌体货物和功能。