Pathogenesis of HIV-associated sensory neuropathy

项目总结 感觉神经病(SN)是人类免疫缺陷病毒1型(HIV-1)最常见的共病 感染患者(hHIV-SN)，影响到全世界3790万艾滋病毒感染患者中的60%。人类免疫缺陷病毒 对现有的止痛疗法特别有抵抗力，现在没有FDA批准的针对HIV的 由于对HHIV-SN的发病机制了解不深，目前尚无止痛药可用。为了发展成疾病- 针对HIV-SN的特异性和机制治疗，我们必须充分阐明其潜在的机制。 健康皮肤主要由蛋白基因产物9.5(PGP9.5+)标记的伤害性感受器产生 伤害性感受和PGP9.5+伤害性感受器的变性是hHIV-SN的重要病理标志。生长 相关蛋白(GAP43)标记新萌发的伤害性感受器(GAP43+)。PGP9.5+和GAP43+伤害性感受器 对胶质细胞源性神经营养因子(GDNF)和神经生长有明显的神经营养依赖性 神经生长因子(NGF)及GDNF和NGF的表达均受Wnt5a调控。WNT5A是一种秘密的 Wnt家族中的信号蛋白，在轴突重塑中发挥重要作用，也是特异的上调- 在HIV-SN慢性疼痛患者的脊髓中进行调节。我们的出版物报道了gp120，一个 HIV-1包膜糖蛋白在gp120诱导的神经病理性疼痛中起致病作用 小鼠SN(mHIV-SN)和hHIV-SN患者。Gp120诱导大鼠脑内神经元Wnt5a异常激活 感觉神经元和脊髓内神经元与坐骨神经痛的发生密切相关 在老鼠和艾滋病毒感染的患者中也是如此。重要的是，我们的初步数据显示，WNT5a特异性 拮抗剂Box5可阻断mHIV-SN相关的疼痛和病理。有趣的是，在mHIV-SN和 HHIV-SN，随着PGP9.5+伤害性感受器退变的进展，甚至接近失神经，慢性疼痛 保持或恶化，而不是解决。这一现象表明，HIV-SN患者的慢性疼痛 由另一种新型伤害性感受器介导，萌芽的GAP43+伤害性感受器特异性地介导 与艾滋病毒相关的慢性疼痛。我们的中心假设是：HIV-1 gp120通过激活Wnt5a-1引起mHIV-SN。 NGF介导的GAP43+伤害性感受器的萌发，进而特异性地介导HIV相关的慢性 疼痛。我们将通过使用mHIV-SN小鼠模型在三个目标上验证这一假设。在目标1中，我们将充分 GAP43+伤害性感受器萌发与PGP9.5+伤害性感受器退化的相互作用 MHIV-SN通过使用多种工程小鼠模型。在目标2中，我们将确定gp120诱导的 Wnt5a-NGF途径通过药理学和遗传学途径介导GAP43+伤害性感受器的萌发 接近了。在目标3中，我们将确定Wnt5a拮抗剂的治疗潜力， Tanezumab和GDNF拮抗Box5、NGF治疗gp120 mHIV-SN小鼠模型中的mHIV-SN。 这项研究的结果将有助于阐明HIV-SN的基本机制并阐明其治疗方法 基于Wnt5a-NGF-GAP43萌芽疗法治疗HIV-SN的潜力。

PROJECT SUMMARY Sensory neuropathy (SN) is the most common comorbidity in Human Immunodeficiency Virus-1(HIV-1) infected-patients (hHIV-SN), which affects 60% of the 37.9 million HIV infected patients in this world. hHIV-SN is particularly resistant to existing pain relief therapies and now there is no FDA approved HIV specific analgesic available due to poorly understanding of the hHIV-SN pathogenesis. In order to develop disease- specific and mechanism-based therapeutics for hHIV-SN, we must fully elucidate the underlying mechanisms. Healthy skin is mainly innervated by nociceptors labeled by protein gene product 9.5 (PGP9.5+) to generate nociception and the degeneration of PGP9.5+ nociceptor is a critical pathological mark of hHIV-SN. Growth associated protein (GAP43) labels the newly sprouted nociceptor (GAP43+). PGP9.5+ and GAP43+ nociceptors have distinctly neurotrophic dependency on glial cell line-derived neurotrophic factor (GDNF) and nerve growth factor (NGF) respectively and the expression of GDNF and NGF are regulated by Wnt5a. Wnt5a is a secreted signaling protein in the Wnt family that plays an important role in axonal remodeling and is also specifically up- regulated in the spinal cord of HIV-SN patients with chronic pain. Our publication reported that gp120, an envelope glycoprotein of HIV-1, plays a causative role in neuropathic pain occurred both in gp120-induced mouse SN (mHIV-SN) and in hHIV-SN patients. The gp120-caused aberrant activation of neuronal Wnt5a in sensory neuron and in spinal cord are intimately relevant with the development of SN-associated pain in mouse and in HIV-infected patients as well. Importantly, our preliminary data have shown that Wnt5a-specific antagonist, Box5, blocks mHIV-SN-associated pain and pathologies. Interestingly, in both of the mHIV-SN and hHIV-SN, as PGP9.5+ nociceptor degeneration progresses, even close to the point of denervation, chronic pain remains or worsens, instead of resolving. This phenomenon indicates that the chronic pain in HIV-SN must be mediated by an alternate novel nociceptor, the sprouted GAP43+ nociceptor which specifically mediates the HIV-Associated chronic pain. Our central hypothesis is: HIV-1 gp120 causes mHIV-SN by activation of Wnt5a- NGF mediated sprouting of the GAP43+ nociceptor, which in turn specifically mediates HIV associated chronic pain. We will test this hypothesis by using mHIV-SN mouse model in three Aims. In Aim #1, we will fully investigate the interplay of the sprouting of GAP43+ nociceptors and the degenerating of PGP9.5+ nociceptor in mHIV-SN by using multiple engineering mouse models. In Aim #2, we will determine that gp120-induced the sprouting of GAP43+ nociceptor is mediated by Wnt5a-NGF pathway by pharmacological and genetic approaches. In Aim #3, we will determine the therapeutic potential of antagonisms of Wnt5a by its antagonist, Box5, NGF antagonism by tanezumab and GDNF to treat mHIV-SN in the gp120 mHIV-SN mouse model. Results from this research will shed light on the essential mechanisms of HIV-SN and illustrate the therapeutic potential of Wnt5a-NGF-GAP43 sprouting-based approaches for treating HIV-SN.