Pathogenesis of HIV-associated sensory neuropathy

HIV相关感觉神经病的发病机制

• 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
• 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

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.

项目摘要 感觉神经病变（SN）是人类免疫缺陷病毒（HIV-1）最常见的合并症 感染者（hHIV-SN），其影响世界上3790万HIV感染者中的60%。hHIV-SN 对现有的疼痛缓解疗法特别耐药，现在FDA还没有批准的HIV特异性药物。 由于对hHIV-SN发病机制的了解不足，为了发展疾病- 为了找到针对hHIV-SN的特异性和机制性治疗方法，我们必须充分阐明其潜在机制。 健康皮肤主要受蛋白基因产物9.5（PGP9.5+）标记的伤害感受器支配，以产生 HIV-SN的伤害感受性和PGP9.5+伤害感受器的变性是HIV-SN的重要病理标志。增长 相关蛋白（GAP 43）标记新萌发的伤害感受器（GAP 43+）。PGP9.5+和GAP 43+伤害感受器 对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的表达受Wnt 5a的调控。Wnt 5a是一种分泌的 Wnt家族中的信号蛋白，在轴突重塑中起重要作用，也特异性上调- 调节脊髓的HIV-SN患者慢性疼痛。我们的出版物报道说，gp 120， HIV-1的包膜糖蛋白，在gp 120诱导的神经病理性疼痛中起着致病作用。 小鼠SN（mHIV-SN）和hHIV-SN患者。gp 120引起的神经元Wnt 5a异常激活 感觉神经元和脊髓中的神经元与SN相关疼痛的发展密切相关， 小鼠和HIV感染者也是如此。重要的是，我们的初步数据表明，Wnt 5a特异性 拮抗剂Box 5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+伤害感受器变性的进展，甚至接近去神经点，慢性疼痛 仍然存在，而不是解决。这一现象表明，慢性疼痛的HIV-SN必须 由另一种新的伤害感受器介导，发芽的GAP 43+伤害感受器特异性介导 HIV相关的慢性疼痛我们的中心假设是：HIV-1 gp 120通过激活Wnt 5a-1而导致mHIV-SN。 NGF介导GAP 43+伤害感受器的发芽，其反过来特异性介导HIV相关慢性炎症反应。 痛苦我们将在三个目的中通过使用mHIV-SN小鼠模型来检验这一假设。在目标#1中，我们将充分 研究GAP 43+伤害感受器的发芽和PGP9.5+伤害感受器的退化之间的相互作用。 mHIV-SN基因工程小鼠模型。在目标#2中，我们将确定gp 120诱导的 GAP 43+伤害感受器出芽是由Wnt 5a-NGF通路介导的，通过药理学和遗传学研究证实， 接近。在目标#3中，我们将确定Wnt 5a的拮抗剂对其拮抗的治疗潜力， 框5，在gp 120 mHIV-SN小鼠模型中，他尼珠单抗和GDNF治疗mHIV-SN的NGF拮抗作用。 这项研究的结果将阐明HIV-SN的基本机制，并说明治疗方法。 基于Wnt 5a-NGF-GAP 43发芽的方法用于治疗HIV-SN的潜力。