Modeling HIV-1 induced disruption of blood brain barrier integrity in mice

模拟 HIV-1 诱导小鼠血脑屏障完整性破坏

基本信息

批准号：
8648207
负责人：
Letitia Day Jones
金额：
$ 3.58万
依托单位：
UNIVERSITY OF ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-12-01 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8648207
关键词：
AIDS neuropathy Address Adult Agonist Animal Model Anti-Inflammatory Agents Anti-inflammatory Astrocytes Blood - brain barrier anatomy Blood Platelets Brain Brain region CD40 Antigens Cell Count Cerebrospinal Fluid Complex DNA Data Development Disease Endothelial Cells Erinaceidae Exclusion Extravasation Genes Genetic Transcription Genome Glioma HIV HIV-1 Homeostasis Human Hypertrophy In Vitro Individual Infection Infiltration Inflammation Inflammation Mediators Injury Integration Host Factors Knowledge Life Link Measures Microscopy Modeling Murine leukemia virus Mus Neuraxis Neurocognitive Neurodegenerative Disorders Neurologic Oncogenes Patients Pattern Peripheral Permeability Plasma Platelet Activation Play Process Proteins Proteolytic Processing Recruitment Activity Reporting Resistance Risk Role Secondary to Signal Transduction Sodium Fluorescein Sonic Hedgehog Pathway Source Staining method Stains TNFRSF5 gene TNFSF5 gene Testing Tracer Trans-Activators Up-Regulation Viral Viral Proteins Virion antiretroviral therapy brain tissue human SMO protein imaging modality in vivo migration monocyte new therapeutic target novel novel therapeutic intervention novel therapeutics public health relevance receptor transcription factor

项目摘要

DESCRIPTION (provided by applicant): HIV-1 infected individuals on combination antiretroviral therapy (cART) are living longer than the pre-cART era, however these individuals are at an increased risk of developing neurocognitive disorders referred to as HIV-1-associated neurocognitive disorders (HAND). HIV-1 infects a great number of cells, yielding proviral DNA. And while cART reduces viral replication, it has no effect on these early viral gene products such as transactivator of transcription (Tat). Tat upregulates inflammatory mediators, stimulating peripheral monocytes to permeate into the central nervous system (CNS). The underlying mechanisms as to how monocytes are able to cross the blood brain barrier (BBB) remain elusive. Previously, our lab has shown that in HAND patients, their cerebrospinal fluid (CSF) and plasma contained abnormally high levels of soluble CD40L (sCD40L) and we have shown that mice injected with physiologically relevant concentrations of Tat had significantly greater levels of sCD40L in their plasma than non-treated mice. In addition, our lab has reported that CD40L receptor, CD40, were present on brain microvascular endothelial cells (BMVEC) and thus this interaction promoted the infiltration of monocytes across the BBB, in vitro. Further, our in vivo studies revealed that Tat induces BBB permeability in mice in a CD40L dependent manner as a result of atypical activation of platelets, a major source of sCD40L, because BBB permeability is reversed after platelet depletion. Overall, these data provide me with a rational framework to test my hypothesis that the virally encoded proteins induce CD40-CD40L signaling to disrupt neurovascular homeostasis and thereby compromising BBB integrity, yielding subsequent neurologic damages that are consistent with the CNS manifestations associated with HAND. The development of new therapeutic approaches can be expected at the completion of this study to address HAND and possibly other neurocognitive disorders not HAND related.

描述（由申请人提供）：接受联合抗逆转录病毒治疗 (cART) 的 HIV-1 感染者的寿命比 cART 之前的时代更长，但是这些人患神经认知障碍（称为 HIV-1 相关神经认知障碍）的风险增加疾病（手）。 HIV-1 感染大量细胞，产生原病毒 DNA。虽然 cART 减少病毒复制，但它对这些早期病毒基因产物（例如转录反式激活因子 (Tat)）没有影响。 Tat 上调炎症介质，刺激外周单核细胞渗透到中枢神经系统 (CNS)。单核细胞如何穿过血脑屏障（BBB）的潜在机制仍然难以捉摸。此前，我们的实验室已经证明，在 HAND 患者中，他们的脑脊液 (CSF) 和血浆中含有异常高水平的可溶性 CD40L (sCD40L)，并且我们已经证明，注射生理相关浓度的 Tat 的小鼠体内的 sCD40L 水平显着更高。血浆比未治疗的小鼠。此外，我们的实验室报告说，CD40L 受体 CD40 存在于脑微血管内皮细胞 (BMVEC) 上，因此这种相互作用在体外促进了单核细胞跨 BBB 的浸润。此外，我们的体内研究表明，由于血小板（sCD40L 的主要来源）的非典型激活，Tat 以 CD40L 依赖性方式诱导小鼠 BBB 通透性，因为血小板耗尽后 BBB 通透性发生逆转。总的来说，这些数据为我提供了一个合理的框架来检验我的假设，即病毒编码的蛋白诱导 CD40-CD40L 信号传导破坏神经血管稳态，从而损害 BBB 完整性，产生与 HAND 相关的 CNS 表现一致的后续神经损伤。本研究完成后，预计将开发出新的治疗方法来解决 HAND 以及可能与 HAND 无关的其他神经认知障碍。