Pathogenesis of HIV-associated sensory neuropathy

HIV相关感觉神经病的发病机制

• 批准号: 10670967
• 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/10670967
• 关键词: Ablation; Acquired Immunodeficiency Syndrome; Acute; Affect; Afferent Neurons; Agonist; Analgesics; Antibodies; Axon; Back; Calcitonin Gene-Related Peptide; 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; Longevity; Measures; Mediating; Mediator; Modeling; Mus; Nerve Growth Factor Pathway; Nerve Growth Factors; Neurons; Neuropathy; Nociception; Nociceptors; Pain; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Peripheral; 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; Treatment Efficacy; Up-Regulation; afferent nerve; allodynia; antagonist; 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; pharmacologic; 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（SN）是人免疫缺陷病毒1（HIV-1）中最常见的合并症 感染患者（HHIV-SN）影响了3790万艾滋病毒感染的患者中的60％。 HHIV-SN 特别抗现有的缓解疼痛疗法，现在没有FDA批准的艾滋病毒特异性 由于对HHIV-SN发病机理的了解不足，可镇痛。为了发展疾病 - 针对HHIV-SN的特定和基于机制的治疗剂，我们必须完全阐明基本机制。 健康的皮肤主要由蛋白质基因产物标记的伤害感受器9.5（pgp9.5+）产生 伤害感受和PGP9.5+伤害感受器的变性是HHIV-SN的关键病理标记。生长 相关蛋白（GAP43）标记新发芽的伤害感受器（GAP43+）。 PGP9.5+和GAP43+伤害感受器 对神经胶质细胞系衍生的神经营养因子（GDNF）和神经生长具有明显的神经营养性依赖性 因子（NGF）分别由WNT5A调节GDNF和NGF的表达。 Wnt5a是一个分泌的 Wnt家族中信号蛋白在轴突重塑中起着重要作用，并且也特别上升 在患有慢性疼痛的HIV-SN患者的脊髓中调节。我们的出版物报道GP120， HIV-1的包膜糖蛋白在神经性疼痛中起着致病作用，在GP120诱导的 小鼠SN（MHIV-SN）和HHIV-SN患者。 GP120引起的神经元WNT5A的异常激活 感觉神经元和脊髓与SN相关疼痛的发展密切相关 小鼠和HIV感染患者。重要的是，我们的初步数据表明WNT5A特定于 拮抗剂Box5阻断了MHIV-SN相关的疼痛和病理。有趣的是，在MHIV-SN和 HHIV-SN，随着pgp9.5+伤害感受器的变性，甚至接近慢性疼痛 保持或恶化，而不是解决。这种现象表明HIV-SN的慢性疼痛必须是 由替代小说的伤害感受器介导的，发芽的GAP43+伤害感受器，专门介导 与HIV相关的慢性疼痛。我们的中心假设是：HIV-1 GP120通过激活Wnt5a-引起MHIV-SN。 NGF介导的GAP43+伤害感受器的发芽，进而特别介导HIV相关的慢性 疼痛。我们将通过三个目标使用MHIV-SN小鼠模型来检验该假设。在AIM＃1中，我们将完全 研究GAP43+伤害感受器的发芽的相互作用和PGP9.5+伤害感受器的退化 MHIV-SN使用多个工程鼠标模型。在AIM＃2中，我们将确定GP120引起的 GAP43+ Nocteptor的发芽是由WNT5A-NGF途径介导的药理和遗传学 方法。在AIM＃3中，我们将确定Wnt5a对拮抗剂的拮抗剂的治疗潜力， Box5，Tanezumab和GDNF在GP120 MHIV-SN小鼠模型中处理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，并说明治疗性 基于WNT5A-NGF-GAP43发芽的方法的潜力，用于治疗HIV-SN。

项目成果

Circulating exosomes from Alzheimer's disease suppress VE-cadherin expression and induce barrier dysfunction in recipient brain microvascular endothelial cell.

来自阿尔茨海默病的循环外泌体抑制 VE-钙粘蛋白表达并诱导受体脑微血管内皮细胞屏障功能障碍。

• DOI: 10.1101/2023.04.03.535441
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Bei,Jiani;Miranda-Morales,ErnestoG;Gan,Qini;Qiu,Yuan;Husseinzadeh,Sorosh;Liew,JiaYi;Chang,Qing;Krishnan,Balaji;Gaitas,Angelo;Yuan,Subo;Felicella,Michelle;Qiu,WeiQiao;Fang,Xiang;Gong,Bin
• 通讯作者: Gong,Bin