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

描述（由申请人提供）：数百万感染艾滋病毒的人类患者遭受慢性疼痛。然而，导致这种破坏性神经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，并开发基于合理的有效疗法。本申请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，我们发现发展为慢性疼痛的HIV患者在脊髓背角（SCDH）表现出戏剧性的星形胶质细胞活化;这在HIV患者中没有看到，否则是相似的，但没有经历慢性疼痛。在这项研究中，我们的目的是阐明星形胶质细胞激活的机制和病理意义的发展过程中的HIV gp 120（一种主要的HIV神经毒素蛋白）诱导的疼痛的小鼠模型。我们提出，gp 120激活星形胶质细胞在SCDH通过一种机制，涉及神经元到星形胶质细胞的信号蛋白，Wnt 5a，和Wnt 5a调节的星形胶质细胞激活促进gp 120诱导的疼痛的发展。这一假设将在三个具体目标中得到检验。在目标#1中，我们将确定SCDH中神经元Wnt 5a对gp 120诱导星形胶质细胞活化的需求。在目标#2中，我们将测试Wnt 5a通过刺激ROR 2/JNK信号通路激活星形胶质细胞的想法。在目标#3中，我们将确定Wnt 5a调节的星形胶质细胞活化在小鼠中gp 120诱导的疼痛的发病机制中的参与。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。该结果将为星形胶质细胞激活机制及其在HIV相关慢性疼痛中的致病作用提供重要见解。所获得的知识，预计将促进艾滋病毒相关的慢性疼痛的合理的医学发展。

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.