Pathogenesis of HIV-associated sensory neuropathy

HIV相关感觉神经病的发病机制

基本信息

批准号：
10403207
负责人：
Subo Yuan
金额：
$ 40万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-30 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10403207
关键词：
Acquired Immunodeficiency Syndrome Acute Affect Afferent Neurons Agonist Analgesics Antibodies Axon Back Calcitonin Gene-Related Peptide Cell Line Clinical Complication Data Denervation Dependence Development Disease Engineering Exhibits FDA approved Family Gene Proteins Glycoproteins Growth Growth Associated Protein 43 HIV HIV Envelope Protein gp120 HIV-1 Human Infection Label Ligation Light Longevity Measures Mediating Mediator of activation protein Modeling Mus Nerve Growth Factor Pathway Nerve Growth Factors Neurons Neuropathy Nociception Nociceptors Pain Pathogenesis Pathologic Pathology Pathway interactions Patients Peripheral Pharmacology Phase Physiological Play Posterior Horn Cells Proteins Publications Reporter Reporting Research Resistance Role Severities Signaling Protein Skin Spinal Cord Spinal Cord Contusions Spinal Ganglia Spinal cord injury Spinal cord posterior horn Spinal nerve structure Testing Therapeutic Tomatoes Treatment Efficacy Up-Regulation afferent nerve allodynia base chronic pain chronic pain patient comorbidity conditional knockout effective therapy experience genetic approach glial cell-line derived neurotrophic factor mouse model nerve supply nervous system disorder neurotrophic factor novel pain patient pain relief painful neuropathy planar cell polarity prevent sensory neuropathy therapeutic evaluation

项目摘要

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.

项目概要感觉神经病 (SN) 是人类免疫缺陷病毒 1 (HIV-1) 最常见的合并症感染者 (hHIV-SN)，影响着全球 3790 万 HIV 感染者中的 60%。 hHIV病毒SN 对现有的止痛疗法特别有抵抗力，而且现在还没有 FDA 批准的 HIV 特异性药物由于对 hHIV-SN 发病机制了解甚少，因此无法使用止痛药。为了发展疾病—— 对于 hHIV-SN 的特异性和基于机制的治疗，我们必须充分阐明其潜在机制。健康的皮肤主要受蛋白质基因产物9.5（PGP9.5+）标记的伤害感受器支配，产生 PGP9.5+伤害感受器的伤害感受和变性是hHIV-SN的重要病理标志。生长相关蛋白 (GAP43) 标记新萌芽的伤害感受器 (GAP43+)。 PGP9.5+ 和 GAP43+ 伤害感受器对神经胶质细胞源性神经营养因子（GDNF）和神经生长具有明显的神经营养依赖性 GDNF和NGF的表达分别受Wnt5a调节。 Wnt5a是一种分泌型 Wnt 家族中的信号蛋白，在轴突重塑中发挥重要作用，并且还具有特异性上调作用在患有慢性疼痛的 HIV-SN 患者的脊髓中受到调节。我们的出版物报道了 gp120， HIV-1 的包膜糖蛋白，在 gp120 诱导的神经性疼痛中起着致病作用小鼠 SN (mHIV-SN) 和 hHIV-SN 患者。 gp120 导致神经元 Wnt5a 异常激活感觉神经元和脊髓中的感觉神经元与 SN 相关疼痛的发展密切相关小鼠和艾滋病毒感染者也是如此。重要的是，我们的初步数据表明 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+ 伤害感受器变性进展，甚至接近去神经支配点，慢性疼痛仍然存在或恶化，而不是解决。这一现象表明 HIV-SN 的慢性疼痛一定是由另一种新型伤害感受器介导，即发芽的 GAP43+ 伤害感受器，专门介导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- 导致 mHIV-SN NGF 介导 GAP43+ 伤害感受器的萌芽，进而特异性介导 HIV 相关慢性疼痛。我们将通过使用 mHIV-SN 小鼠模型在三个目标中检验这一假设。在目标#1中，我们将充分研究 GAP43+ 伤害感受器的萌芽和 PGP9.5+ 伤害感受器退化的相互作用 mHIV-SN 通过使用多个工程小鼠模型。在目标 #2 中，我们将确定 gp120 诱导的 GAP43+伤害感受器的萌芽是由Wnt5a-NGF通路通过药理学和遗传介导的接近。在目标#3中，我们将确定 Wnt5a 拮抗剂的拮抗作用的治疗潜力， Box5，tanezumab 和 GDNF 对抗 NGF 来治疗 gp120 mHIV-SN 小鼠模型中的 mHIV-SN。这项研究的结果将揭示 HIV-SN 的基本机制并说明治疗方法基于 Wnt5a-NGF-GAP43 萌芽的方法治疗 HIV-SN 的潜力。