Wnt signaling in glial activation during HIV-associated chronic pain pathogenesis

HIV相关慢性疼痛发病机制中神经胶质激活中的Wnt信号传导

• 批准号: 8846150
• 负责人: SHAO-JUN TANG
• 金额: $ 38.25万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8846150
• 关键词: Abbreviations; Acquired Immunodeficiency Syndrome; Animals; Astrocytes; Binding; CXCR4 Receptors; Cellular biology; Chemokine (C-C Motif) Receptor 5; Complication; Data; Development; Employee Strikes; Family; Glial Fibrillary Acidic Protein; Goals; HIV; HIV Envelope Protein gp120; HIV Seropositivity; HIV-1; Human; Hyperalgesia; Injection of therapeutic agent; Interleukin-1; Intrathecal Injections; Investigation; Knock-out; Knowledge; Lead; Life; MAPK8 gene; Mainstreaming; Mechanics; Medicine; Modeling; Molecular; Molecular Abnormality; Molecular Biology; Mus; N-Methyl-D-Aspartate Receptors; Neuroglia; Neurologic; Neurons; Neuropathogenesis; Neurotoxins; Orphan; Pain; Pain Research; Pathogenesis; Pathologic Processes; Pathway interactions; Patients; Pharmacology; Population; Process; Proteins; RORA gene; Receptor Protein-Tyrosine Kinases; Research; Role; Signal Pathway; Signal Transduction; Signaling Protein; Source; Spinal Cord; Spinal cord posterior horn; Synapses; TNF gene; Tamoxifen; Testing; Toxin; Tumor Necrosis Factor-alpha; Work; base; calmodulin-dependent protein kinase II; chronic pain; clinically relevant; cytokine; design; dorsal horn; effective therapy; experience; improved; insight; interdisciplinary approach; knockout gene; member; mouse model; prevent; receptor; recombinase

DESCRIPTION (provided by applicant): Millions of HIV-infected human patients suffer chronic pain. However, the pathological process leading to this devastating neurological condition is unclear, and an effective therapy is not available. Our long-term goals are to better understand the mechanism of HIV-associated pain and to develop rationale-based effective therapies. The objective of this application is to determine the role of glia, especially astrocytes, in the neuropathogenesis of HIV pain. In preliminary studies, we found that the HIV patients who developed chronic pain manifested dramatic astrocyte activation in the spinal cord dorsal horn (SCDH); this was not seen in the HIV patients who otherwise were similar but did not experience chronic pain. In this study, we aim to elucidate the mechanism and pathological significance of the astrocyte activation during the development of HIV gp120 (a major HIV neurotoxin protein)-induced pain in the mouse model. We propose that gp120 activates astrocytes in the SCDH through a mechanism that involves a neuron-to-astrocyte signaling protein, Wnt5a, and that the Wnt5a- regulated astrocyte activation promotes the development of gp120-induced pain. This hypothesis will be tested in three Specific Aims. In Aim #1, we will determine the requirement of neuronal Wnt5a in the SCDH for gp120 to induce astrocyte activation. In Aim #2, we will test the idea that Wnt5a activates astrocytes by stimulating a ROR2/JNK signaling pathway. In Aim #3, we will determine the involvement of Wnt5a-regulated astrocyte activation in the pathogenesis of gp120-induced pain in mice. The proposed research will use an integrated multidisciplinary approach of molecular and cell biology, pharmacology and conditional gene knockout. The results will provide important insights into the mechanism of astrocyte activation and its pathogenic role in HIV- associated chronic pain. The knowledge obtained is expected to facilitate the development of rationale-based medicine for HIV-associated chronic pain.

描述（由申请人提供）：数百万艾滋病毒感染的人类患者遭受慢性疼痛。然而，导致这种破坏性神经系统疾病的病理过程尚不清楚，也没有有效的治疗方法。我们的长期目标是更好地了解hiv相关疼痛的机制，并开发基于理性的有效治疗方法。本应用的目的是确定神经胶质细胞，特别是星形胶质细胞在HIV疼痛的神经发病机制中的作用。在初步研究中，我们发现出现慢性疼痛的HIV患者在脊髓背角（SCDH）表现出明显的星形胶质细胞激活；这在其他方面相似但没有经历慢性疼痛的HIV患者中没有看到。在本研究中，我们旨在阐明星形胶质细胞在HIV gp120（一种主要的HIV神经毒素蛋白）诱导的小鼠疼痛模型中激活的机制和病理意义。我们提出gp120激活SCDH中的星形胶质细胞的机制涉及神经元-星形胶质细胞信号蛋白Wnt5a，并且Wnt5a调节的星形胶质细胞激活促进了gp120诱导的疼痛的发展。这一假设将在三个具体目标中进行测试。在Aim #1中，我们将确定SCDH中神经元Wnt5a对gp120诱导星形胶质细胞激活的要求。在Aim #2中，我们将验证Wnt5a通过刺激ROR2/JNK信号通路激活星形胶质细胞的观点。在Aim #3中，我们将确定wnt5a调控的星形细胞激活在gp120诱导的小鼠疼痛发病机制中的作用。拟议的研究将使用分子和细胞生物学、药理学和条件基因敲除的综合多学科方法。这些结果将为星形胶质细胞激活的机制及其在HIV相关慢性疼痛中的致病作用提供重要的见解。所获得的知识有望促进基于理性的艾滋病毒相关慢性疼痛药物的发展。