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

• 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
• 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

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，但通常诊断不足和/或治疗不足。不幸的是，在目前广泛的HIV/AIDS（获得性免疫缺陷综合征）研究中，DSP是一个研究不足的领域，几乎没有可用的动物模型。先前已经表明，感染LP-BM 5（一种鼠逆转录病毒分离物）的C57 BL/6小鼠发展出与感染HIV的人相似的严重获得性免疫缺陷综合征，因此称为鼠AIDS（MAIDS）。LP-BM 5感染还在C57 BL/6小鼠中诱导CNS脑病和认知缺陷，这通过用抗逆转录病毒剂叠氮胸苷治疗来预防。我们的初步实验表明，LP-BM 5诱导显著的后肢机械超敏反应和脚垫皮肤中的外周神经纤维的损失，周围神经病变的迹象，沿着MAIDS的发展，这表明LP-BM 5感染可能是HIV/AIDS相关的疼痛性周围神经病变的潜在啮齿动物模型。目前的建议是第一次尝试在C57 BL/6小鼠中表征LP-BM 5诱导的周围神经病变并研究LP-BM 5诱导的神经病变的机制。我们假设外周LP-BM 5病毒感染导致疼痛性周围神经病变，表现为易感C57 BL/6小鼠的后肢机械超敏反应和脚垫表皮内神经纤维（IENF）密度降低，脊髓小胶质细胞LP-BM 5感染及其直接或间接诱导小胶质细胞CD 40上调有助于LP-BM 5诱导的周围神经病变。中心假设将通过三个特定目的进行检验：1）表征LP-BM 5诱导的周围神经病变发展的时间进程; 2）鉴定LP-BM 5在腰髓中的特异性细胞靶点; 3）确定脊髓小胶质细胞CD40在LP-BM 5诱导的周围神经病变中的作用。已知CD154（CD40L）-CD40相互作用在MAIDS特征的发展中是关键的。此外，CD40信号传导和CNS小胶质细胞在HIV脑炎以及外周神经损伤诱导的神经病变的发病机制中是至关重要的。评估小胶质细胞CD40的作用将进一步提供参与LP-BM 5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关于逆转录病毒感染引起的神经病变的进一步知识，这可能导致更好地理解和更有效地治疗HIV感染相关的疼痛性周围神经病变。 公共卫生相关性：据估计，在2007年年底，全世界有3 300万人感染艾滋病毒/获得性免疫缺陷综合症（艾滋病）（2007年联合国艾滋病流行病最新报告），因此，人们更加关注与艾滋病毒感染有关的多种并发症的治疗。疼痛性远端对称性多发性神经病（DSP）是最常见的HIV感染相关性周围神经病变，由于缺乏有效的动物模型，其诊断和治疗往往不足。目前的研究为建立人类HIV感染相关DSP的啮齿动物模型带来了巨大的潜力，并可能导致更有效的治疗。