Monocyte/macrophage traffic and peripheral nerve pathogenesis

单核细胞/巨噬细胞交通和周围神经发病机制

• 批准号: 8467482
• 负责人: Tricia Helen Burdo
• 金额: $ 41.98万
• 依托单位: BOSTON COLLEGE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8467482
• 关键词: Acquired Immunodeficiency Syndrome; Active Sites; Address; Anti-Retroviral Agents; Automobile Driving; Biological Markers; Blood; Bone Marrow; Bromodeoxyuridine; Chronic; Clinical; Clinical Markers; Complication; Disease; Disease Progression; Fiber; Fluorescent Dyes; HIV; HIV Infections; Human; Immune; Immunosuppression; Infection; Inflammation; Inflammatory; Investigation; Label; Lesion; Link; Macaca; Macaca mulatta; Macrophage Activation; Measures; Mediating; Modeling; Nerve Fibers; Neurologic; Neuronal Injury; Neuropathy; Pain; Pathogenesis; Pathology; Patients; Peripheral; Peripheral Nerves; Peripheral Nervous System Diseases; Physiologic pulse; Prevalence; Recruitment Activity; Regulation; Reporting; Role; S100A9 gene; SIV; Spinal Ganglia; System; Testing; Tissues; Viral; antiretroviral therapy; clinically relevant; density; macrophage; monocyte; therapy development; trafficking

DESCRIPTION (provided by applicant): Peripheral neuropathy is the most common neurological complication of HIV infection with the prevalence of neuropathy as high as 69.4% in HIV-infected patients. Increasing reports from humans highlight the contribution of macrophage activation and dorsal root ganglia (DRG) inflammation to the persistence of pathological pain in peripheral neuropathy, but the demonstration of macrophage traffic and DRG macrophages as a viral reservoir is not known. The pathogenesis of peripheral neuropathy is incompletely understood, but it is likely macrophage-mediated. In this application, we will use a SIV rhesus macaque model of AIDS to determine if: 1) continual monocyte traffic to DRGs drives peripheral neuropathy pathogenesis and effective anti-retroviral therapy (ART) will minimize this effect, 2) the ratio of M1/M2 regulatory predicts early versus chronic peripheral nerve lesions and effective ART will alter this ratio, 3) clinically relevant biomarkers (sCD163, BrdU, IENF) are linked to DRG pathology, and 4) DRG macrophages are viral reservoirs with and without ART. Successful completion of studies in this application will allow us to define: 1) monocyte/ macrophage mechanisms of DRG pathology, 2) monocyte/macrophage immune regulation during PNS disease, 3) clinical markers of peripheral nerve disease and 4) DRG macrophages as active sites of viral replication and as viral reservoirs. The overall hypothesis of the application is continual monocyte/macrophage traffic drives DRG pathogenesis and clinically relevant biomarkers and IENF effectively predict peripheral nerve pathology with and without ART. Studies in aim 1 will define the role of monocyte traffic and macrophage turnover driving PNS pathogenesis and establish a correlation between DRG damage and IENF loss with the hypothesis that monocyte traffic to DRGs mediates damage and correlates to PNS pathology. A subaim will address the hypothesis that the ratio of M1/M2 macrophages predicts early versus chronic PNS lesions. Additionally, DRG macrophages as active sites of viral replication and/or as latent viral reservoirs will be defined in this aim. Studies in aim 2 will define the role of systemic viral suppression to: 1) stop or slow PNS disease; 2) stop or slow macrophage recruitment to DRGs and 3) to clear DRG viral reservoirs. The hypothesis driving aim 2 is that systemic viral suppression by ART will slow PNS disease progression by inhibiting monocyte traffic to the DRGs and potentially clear DRG viral reservoirs. The studies described in this application provide an exciting opportunity to define the role of monocyte/macrophage traffic and macrophage activation in PNS disease and neuronal injury and the role of systemic viral immune suppression. The studies proposed here will provide new avenues of investigation into the development of therapies targeting the monocyte/macrophage in HIV peripheral neuropathy. PUBLIC HEALTH RELEVANCE: HIV-associated peripheral neuropathy is the most common neurological complication of HIV infection with prevalence as high as 69.4% in HIV-infected patients. In this application, we will use a SIV rhesus macaque model of AIDS to define the role of monocyte traffic driving peripheral nerve pathogenesis, to predict the formation of early versus chronic peripheral nerve lesions using the ratio of M1/M2 regulatory macrophages and to examine clinical biomarkers (sCD163, BrdU, IENF) linked to DRG pathology. Studies in this application will allow us to define mechanisms of DRG pathology, monocyte/macrophage immune regulation during peripheral nerve system disease and the ability of effective antiretroviral therapy to stop monocyte traffic and to clear DRG macrophage reservoirs.

描述（由申请人提供）：周围神经病是HIV感染的最常见神经系统并发症，在HIV感染的患者中神经病的患病率高高达69.4％。人类的报道增加了巨噬细胞激活和背根神经节（DRG）炎症对周围神经病病理疼痛持久性的贡献，但尚不清楚巨噬细胞流量和DRG巨噬细胞作为病毒储量的示范。周围神经病的发病机理未完全理解，但可能是巨噬细胞介导的。 In this application, we will use a SIV rhesus macaque model of AIDS to determine if: 1) continual monocyte traffic to DRGs drives peripheral neuropathy pathogenesis and effective anti-retroviral therapy (ART) will minimize this effect, 2) the ratio of M1/M2 regulatory predicts early versus chronic peripheral nerve lesions and effective ART will alter this ratio, 3) clinically relevant生物标志物（SCD163，BRDU，IENF）与DRG病理相关，而4）DRG巨噬细胞是具有和没有艺术的病毒储层。在本应用中成功完成研究将使我们能够定义：1）DRG病理学的单核细胞/巨噬细胞机制，2）PNS疾病期间的单核细胞/巨噬细胞免疫调节，3）外周神经疾病的临床标志物和4）DRG巨噬细胞作为病毒复制和病毒疗法的活性部位。总体假设 该应用是连续的单核细胞/巨噬细胞交通驱动DRG发病机理和临床相关的生物标志物，而IENF有效地预测了有或没有ART的外围神经病理。 AIM 1中的研究将定义单核细胞流量和巨噬细胞转移的作用，驱动PNS发病机理，并在DRG损伤与IENF损失之间建立相关性与单核细胞流量介导DRGS介导损害并与PNS病理学相关的假设。 Subaim将解决以下假设：M1/M2巨噬细胞的比率可以预测早期与慢性PNS病变的比率。此外，将在此目标中定义DRG巨噬细胞作为病毒复制和/或作为潜在病毒储存的活性位点。 AIM 2中的研究将定义全身病毒抑制的作用：1）停止或缓慢的PNS疾病； 2）停止或减慢巨噬细胞募集到DRG和3）清除DRG病毒库。假设驾驶目的2是，通过抑制DRG的单核细胞流量和潜在的DRG病毒储层，ART被ART抑制的全身性病毒抑制会减慢PNS疾病的进展。本应用中描述的研究为定义单核细胞/巨噬细胞流量和巨噬细胞激活在PNS疾病和神经元损伤以及全身性病毒免疫抑制的作用的作用提供了令人兴奋的机会。此处提出的研究将为针对HIV外周神经病中靶向单核细胞/巨噬细胞的疗法的发展提供新的研究途径。 公共卫生相关性：与HIV感染的HIV感染最常见的HIV感染的神经系统并发症，患病率高于69.4％。在此应用中，我们将使用SIV恒河猕猴的辅助模型来定义单核细胞交通驱动周围神经发病机理的作用，以预测使用M1/M2调节性巨噬细胞和检查临床生物标志物（SCD163，brdu ford to drow）的早期和慢性周围神经病变的形成。在本应用中的研究将使我们能够定义DRG病理学的机制，周围神经系统疾病期间的单核细胞/巨噬细胞免疫调节，以及有效的抗逆转录病毒疗法停止单核细胞流量和清除DRG巨噬细胞储量的能力。