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）：远端对称多发性病变（DSP）是人类免疫缺陷病毒（HIV）感染相关的周围神经病的最常见形式，但经常与疼痛有关，但是它通常被诊断不足和/或不足。不幸的是，在广泛的当前艾滋病毒/艾滋病（获得性免疫缺陷综合症）研究中，DSP是一个研究的领域，几乎没有可用的动物模型。以前已经显示，感染了LP-BM5的C57BL/6小鼠，鼠逆转录病毒分离株，形成一种类似于感染HIV的人类的严重获得的免疫缺陷综合征，因此鼠（女仆）一词。 LP-BM5感染还会诱导C57BL/6小鼠的中枢神经系统脑病和认知缺陷，这些缺陷通过用抗逆转录病毒剂偶氮胺治疗而预防的C57BL/6小鼠。我们的初步实验表明，LP-BM5诱导了脚垫皮肤中的明显后肢机械性超敏反应和外周神经纤维的丧失，外周神经病的迹象以及女仆的发展，表明LP-BM5感染可能是HIV/AID艾滋病的潜在幼虫模型，可能是伴有疼痛的Neuropy疼痛的Neuropy。当前的建议是表征LP-BM5诱导的周围神经病变的首次尝试，并研究了LP-BM5诱导的神经病中的机制。我们假设周围LP-BM5病毒感染会导致疼痛的周围神经病，以后肢的机械性超敏反应和脚部垫内填充性神经纤维（IENF）的降低，易感C57BL/6小鼠和脊柱微胶质细胞LP-BM5感染量，并划分了sirctial lp-bm5感染。调节有助于LP-BM5诱导的周围神经病。中心假设将通过三个特定目的进行检验：1）表征LP-BM5诱导的周围神经病的时间过程； 2）确定腰脊髓中LP-BM5的特定细胞靶标； 3）确定脊髓小胶质细胞CD40在LP-BM5诱导的周围神经病中的作用。 CD154（CD40L）-CD40相互作用对于女仆特征的发展至关重要。同样，CD40信号传导和中枢神经系统小胶质细胞在HIV脑炎的发病机理以及周围神经损伤引起的神经病变方面至关重要。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的进一步知识，这可能会导致对与HIV感染相关的疼痛外周神经病的更好理解和更有效的治疗方法。 公共卫生相关性：据估计，全世界有3,300万人在2007年底患有艾滋病毒/获得性免疫缺陷综合症（AIDS）（2007年联合国AIDS AIDS流行更新报告），因此，更多的关注集中在众多与HIV相关相关的复杂性的治疗上。作为与HIV感染相关的周围神经病的最常见形式，由于缺乏可用的动物模型，疼痛的远端远端远端对称多神经病（DSP）通常部分被诊断不足和/或缺乏部分治疗。当前的研究具有建立与人类相关的DSP的啮齿动物模型的巨大潜力，并可能导致更有效的治疗方法。