Murine AIDS (LP-BM5) viral infection induced peripheral neuropathy - Role of CNS

小鼠艾滋病 (LP-BM5) 病毒感染引起的周围神经病变 - 中枢神经系统的作用

基本信息

批准号：
7938606
负责人：
Ling Cao
金额：
$ 17.07万
依托单位：
UNIVERSITY OF NEW ENGLAND
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-25 至 2012-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7938606
关键词：
Acquired Immunodeficiency Syndrome Affect Animal Model Anti-Retroviral Agents Area Attention C57BL/6 Mouse Chronic Disease Cognitive deficits Development Diagnosis Disease Distal Encephalopathies Epidemic Flow Cytometry Goals HIV HIV encephalitis Human Hypergammaglobulinemia Hypersensitivity Immunohistochemistry Immunologic Deficiency Syndromes Infection Knockout Mice Knowledge Lead Leukocytes Life Limb structure Lumbar spinal cord structure Measurement Mechanics Microglia Modeling Modification Murine Acquired Immunodeficiency Syndrome Mus Nerve Fibers Neuropathy Pain Pathogenesis Peripheral Peripheral Nerves Peripheral Nervous System Diseases Peripheral nerve injury Polyneuropathy Reporting Research Reverse Transcription Rodent Model Role Signal Transduction Skin Spinal Cord Spleen Splenomegaly TNFRSF5 gene TNFSF5 gene Testing Text Time Tissues United Nations Up-Regulation Update Viral Viral Load result Viral Proteins Virus Diseases Zidovudine cellular targeting density design effective therapy foot painful neuropathy prevent public health relevance research study

项目摘要

DESCRIPTION (provided by applicant): Distal symmetrical polyneuropathy (DSP) is the most common form of human immunodeficiency virus (HIV) infection-associated peripheral neuropathy and is frequently associated with pain, however it is often under-diagnosed and/or under-treated. Unfortunately, amongst the extensive current HIV/AIDS (acquired immunodeficiency syndrome) research, DSP is an understudied area with few animal models available. It has been previously shown that C57BL/6 mice infected with LP-BM5, a murine retroviral isolate, develop a severe acquired immunodeficiency syndrome similar to humans infected with HIV, hence the term murine AIDS (MAIDS). LP-BM5 infection also induces CNS encephalopathy and cognitive deficits in C57BL/6 mice that are prevented by treatment with the anti-retroviral agent azidothymidine. Our preliminary experiment shows that LP-BM5 induced significant hind limb mechanical hypersensitivity and loss of peripheral nerve fibers in the foot pad skins, signs of peripheral neuropathy, along with the development of MAIDS, suggesting that LP-BM5 infection could be a potential rodent model of HIV/AIDS associated painful peripheral neuropathy. The current proposal is the first attempt to characterize LP-BM5-induced peripheral neuropathy in C57BL/6 mice and investigate the mechanisms in LP-BM5-induced neuropathy. We hypothesize that peripheral LP-BM5 viral infection leads to a painful peripheral neuropathy, presented as hind limb mechanical hypersensitivity and reduced foot pad intraepidermal nerve fiber (IENF) density in susceptible C57BL/6 mice and that spinal cord microglial LP-BM5 infection and its direct or indirect induction of microglial CD40 up- regulation contribute to LP-BM5-induced peripheral neuropathy. The central hypothesis will be tested through three specific aims: 1) Characterize the time course of the development of LP-BM5-induced peripheral neuropathy; 2) Identify the specific cellular target of LP-BM5 in the lumbar spinal cord; and 3) Determine the role of spinal cord microglial CD40 in LP-BM5-induced peripheral neuropathy. CD154 (CD40L)-CD40 interaction is known to be critical in the development of the features of MAIDS. Also both CD40 signaling and CNS microglia are critical in the pathogenesis of HIV encephalitis as well as peripheral nerve injury-induced neuropathy. Assessing the role of microglial CD40 will further provide underlying mechanisms involved in the LP-BM5-induced peripheral neuropathy. The long-term goal of the proposed study is to provide further knowledge on retroviral infection-induced neuropathy that could lead to a better understanding of, and more effective treatments for, HIV infection-associated painful peripheral neuropathy. PUBLIC HEALTH RELEVANCE: It is estimated that 33 million people worldwide were living with HIV/acquired immunodeficiency syndrome (AIDS) at the end of 2007 (The 2007 United Nations AIDS epidemic update reports), and as such, greater attention is being focused on the treatment of the numerous HIV infection-related complications. As the most common form of HIV infection-associated peripheral neuropathy, painful distal symmetrical polyneuropathy (DSP) is often under-diagnosed and/or under-treated partially due to a lack of available animal models. The current study carries great potential for establishing a rodent model of HIV infection associated DSP in humans and may lead to more effective treatments.

描述（由申请人提供）：远端对称性多发性神经病 (DSP) 是人类免疫缺陷病毒 (HIV) 感染相关周围神经病的最常见形式，通常与疼痛相关，但常常诊断不足和/或治疗不足。不幸的是，在当前广泛的 HIV/AIDS（获得性免疫缺陷综合症）研究中，DSP 是一个研究不足的领域，可用的动物模型很少。此前已有研究表明，感染 LP-BM5（一种鼠逆转录病毒分离株）的 C57BL/6 小鼠会出现与感染 HIV 的人类类似的严重获得性免疫缺陷综合征，因此被称为鼠类艾滋病 (MAIDS)。 LP-BM5 感染还会诱发 C57BL/6 小鼠中枢神经系统脑病和认知缺陷，而用抗逆转录病毒药物叠氮胸苷治疗可以预防这些缺陷。我们的初步实验表明，LP-BM5 诱导显着的后肢机械过敏和足垫皮肤周围神经纤维的损失，周围神经病变的迹象，以及 MAIDS 的发展，表明 LP-BM5 感染可能是一种潜在的啮齿动物模型HIV/AIDS 相关的疼痛性周围神经病。目前的提议是首次尝试在 C57BL/6 小鼠中表征 LP-BM5 诱导的周围神经病变，并研究 LP-BM5 诱导的神经病变的机制。我们假设外周 LP-BM5 病毒感染会导致易感 C57BL/6 小鼠的疼痛性周围神经病变，表现为后肢机械过敏和足垫表皮内神经纤维 (IENF) 密度降低，并且脊髓小胶质细胞 LP-BM5 感染及其直接或间接诱导小胶质细胞 CD40 上调有助于 LP-BM5 诱导的周围神经病变。中心假设将通过三个具体目标进行检验：1）描述 LP-BM5 诱导的周围神经病变发展的时间过程； 2) 识别LP-BM5在腰脊髓中的特异性细胞靶点； 3)确定脊髓小胶质细胞CD40在LP-BM5诱导的周围神经病变中的作用。已知 CD154 (CD40L)-CD40 相互作用对于 MAIDS 特征的发展至关重要。此外，CD40 信号传导和中枢神经系统小胶质细胞在 HIV 脑炎以及周围神经损伤引起的神经病的发病机制中都至关重要。评估小胶质细胞 CD40 的作用将进一步提供参与 LP-BM5 诱导的周围神经病变的潜在机制。拟议研究的长期目标是提供有关逆转录病毒感染引起的神经病变的进一步知识，从而更好地了解 HIV 感染相关的疼痛性周围神经病变并提供更有效的治疗。公共卫生相关性：据估计，截至 2007 年底，全世界有 3300 万人感染艾滋病毒/后天免疫机能丧失综合症 (艾滋病)（2007 年联合国艾滋病流行病最新报告），因此，人们更加关注艾滋病毒/后天免疫机能丧失综合症 (AIDS)。治疗许多与艾滋病毒感染相关的并发症。作为 HIV 感染相关周围神经病最常见的形式，疼痛性远端对称性多发性神经病 (DSP) 经常被诊断不足和/或治疗不足，部分原因是缺乏可用的动物模型。目前的研究对于在人类中建立与 DSP 相关的 HIV 感染啮齿动物模型具有巨大的潜力，并可能带来更有效的治疗方法。