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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

基本信息

批准号：
9088512
负责人：
Tricia Helen Burdo
金额：
$ 32.37万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-30 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9088512
关键词：
Acquired Immunodeficiency Syndrome Active Sites Address Anti-Retroviral Agents Automobile Driving Biological Markers Blood Bone Marrow Bromodeoxyuridine Chronic 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 Viral reservoir Virus Replication antiretroviral therapy clinical biomarkers clinically relevant density macrophage monocyte targeted treatment therapy development trafficking

项目摘要

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.

描述（申请人提供）：周围神经病变是 HIV 感染最常见的神经系统并发症，HIV 感染者中神经病变的患病率高达 69.4%。越来越多的人类报告强调了巨噬细胞激活和背根神经节 (DRG) 炎症对周围神经病变中病理性疼痛持续存在的影响，但巨噬细胞运输和 DRG 巨噬细胞作为病毒库的证据尚不清楚。周围神经病变的发病机制尚不完全清楚，但很可能是巨噬细胞介导的。在此应用中，我们将使用艾滋病的 SIV 恒河猴模型来确定是否：1) 持续单核细胞流向 DRG 驱动周围神经病变发病机制，有效的抗逆转录病毒治疗 (ART) 将最大限度地减少这种影响，2) M1/M2 调节比率预测早期与慢性周围神经病变，有效的 ART 将改变该比率，3) 临床相关生物标志物（sCD163、BrdU、IENF）与 DRG 病理学相关，4) DRG 巨噬细胞是有或没有 ART 的病毒储存库。成功完成本申请的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）周围神经疾病的临床标志物和4）DRG巨噬细胞作为病毒复制的活性位点和病毒库。总体假设为该应用程序是连续的单核细胞/巨噬细胞流量驱动 DRG 发病机制和临床相关生物标志物，并且 IENF 可以有效预测有或没有 ART 的周围神经病理。目标 1 的研究将确定单核细胞运输和巨噬细胞周转在驱动 PNS 发病机制中的作用，并建立 DRG 损伤和 IENF 损失之间的相关性，假设单核细胞向 DRG 的运输介导损伤并与 PNS 病理相关。一个子目标将解决以下假设：M1/M2 巨噬细胞的比率可预测早期与慢性 PNS 病变。此外，DRG 巨噬细胞作为病毒复制的活性位点和/或潜在的病毒储存库将在此目标中定义。目标 2 的研究将明确全身性病毒抑制的作用：1）阻止或减缓 PNS 疾病； 2) 停止或减缓巨噬细胞向 DRG 的募集，3) 清除 DRG 病毒库。驱动目标 2 的假设是，ART 的系统性病毒抑制将通过抑制单核细胞向 DRG 的运输来减缓 PNS 疾病的进展，并可能清除 DRG 病毒库。本申请中描述的研究提供了一个令人兴奋的机会来定义单核细胞/巨噬细胞运输和巨噬细胞激活在三七总皂甙疾病和神经元损伤中的作用以及全身病毒免疫抑制的作用。这里提出的研究将为开发针对 HIV 周围神经病变的单核细胞/巨噬细胞的疗法提供新的研究途径。