HIV Tat-associated Sensory Neuropathy and the Contribution of Toll-like Receptor Pathway

HIV Tat 相关感觉神经病变和 Toll 样受体通路的贡献

• 批准号: 10838798
• 负责人: Ling Cao
• 金额: $ 35.5万
• 依托单位: UNIVERSITY OF NEW ENGLAND
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10838798
• 关键词: Acceleration; Acquired Immunodeficiency Syndrome; Address; Affect; Animal Model; Animals; Anti-Retroviral Agents; Autopsy; Behavior; Behavioral; Bioinformatics; Cells; Chronic Disease; Clinical; Clinical assessments; Data; Detection; Development; Diagnosis; Doxycycline; Drug Combinations; Effectiveness; FDA approved; Genes; Genetic Transcription; Genetically Modified Animals; Goals; HIV; HIV Infections; HIV-1; Health; Highly Active Antiretroviral Therapy; Human; IRAK1 gene; Immunohistochemistry; Individual; Infection; Inflammation; Investigation; Knock-out; Knowledge; Location; Longevity; Lumbar spinal cord structure; Mediating; Modeling; Mus; Neural Conduction; Neurologic; Neuropathy; Outcome; Pain; Pain management; Pathway interactions; Patients; Peripheral Nervous System Diseases; Personal Satisfaction; Persons; Pharmaceutical Preparations; Pharmacotherapy; Physiological; Pre-Clinical Model; Prevalence; Process; Property; Proteins; Publishing; Quality of Care; Quantitative Reverse Transcriptase PCR; RNA; Regulation; Reporting; Resources; Role; Signal Pathway; Signaling Molecule; Testing; Time; Toll-Like Receptor Pathway; Toll-like receptors; Trans-Activators; Transcription Coactivator; Transgenic Mice; Variant; bioinformatics tool; comorbidity; cytokine; drug candidate; drug discovery; genetic regulatory protein; improved; in vivo; nano-string; overexpression; painful neuropathy; receptor binding; recruit; sensory neuropathy; sound; treatment strategy

Summary Peripheral neuropathies are the most frequent neurological complications associated with HIV, within which HIV sensory neuropathy (HIV-SN) is the most common form, affecting nearly half of HIV/AIDS patients with the prevalence ranging from 1.2 – 69.4%. HIV-SN frequently manifests with hard-to-manage pain and is often under-diagnosed and/or under-treated, yet, the large variation in prevalence does not allow for detection of significant differences in prevalence between HAART-exposed vs. HAART-non-exposed individuals. There is no specific FDA-approved treatment for HIV-SN. Tat, trans-activator of transcription, a regulatory protein among the first proteins expressed following HIV infection, is a key activator of HIV transcription and can affect both HIV infected cells and non-infected neighboring cells via its secretion by infected cells. Although human studies are lacking, recent animal studies using two models of doxycycline-inducible HIV-1 Tat transgenic (iTat) mice from our lab and others provided convincing evidence that HIV Tat contributes to the development of HIV-SN. Therefore, in this proposal, we will further investigate the underlying mechanisms of Tat-associated SN. Our preliminary study identified potential regulation of Tat of Toll-like receptor (TLR) signaling pathway. Given the widely accepted involvement of TLR pathway in neuropathic pain and surprising lack of studies exploring the role of TLR pathway in HIV-SN, we will focus on TLR pathway in Tat-associated SN in this study. We will take advantage of bioinformatic tools to identify FDA-approved drugs without significant interactions with existing antiretroviral drugs that could potentially reverse Tat-induced changes in TLR pathway, and then test their effectiveness in treating Tat-associated SN in vivo. Altogether, we hypothesize that TLR signaling pathway is involved in the development of HIV-Tat-associated SN and it is possible to identify potential treatment for HIV-SN by examining existing drugs via a combined bioinformatics and pre-clinical model approach. This will be tested through 2 Specific Aims. Aim 1 will determine the contribution of Tollip (a key regulator of TLR pathway)-regulated TLR pathways in HIV Tat-associated SN using genetically modified animal models in combination with behavioral and physiological tests. Aim 2 will identify potential drugs for HIV-SN by targeting TLR pathway via a combined bioinformatics and pre-clinical model approach. If successful, we will fill in the knowledge gaps regarding Tat-associated SN and TLRs’ role in HIV-SN. Our comprehensive combination drug discovery strategy will help identify potential drugs for HIV-SN, which can be further tested in other animal models before clinical assessment. Throughout the process, we will prioritize drug candidates that are mechanistically-sound, and potentially easily accessible to all patients.

概括 周围神经病是与 HIV 相关的最常见的神经系统并发症，其中 HIV 感觉神经病 (HIV-SN) 是最常见的形式，影响近一半的 HIV/AIDS 患者 患病率范围为 1.2 – 69.4%。 HIV-SN 经常表现为难以控制的疼痛，并且常常 诊断不足和/或治疗不足，然而，患病率的巨大差异不允许检测 暴露于HAART的个体与未暴露于HAART的个体之间的患病率存在​​显着差异。有 FDA 没有批准针对 HIV-SN 的具体治疗方法。 Tat，转录反式激活因子，一种调节蛋白 HIV 感染后首先表达的蛋白质之一，是 HIV 转录的关键激活剂，可以影响 HIV感染的细胞和未感染的邻近细胞均通过受感染细胞的分泌作用。虽然是人类 缺乏研究，最近使用两种多西环素诱导的 HIV-1 Tat 转基因模型进行动物研究 我们实验室和其他实验室的 (iTat) 小鼠提供了令人信服的证据，证明 HIV Tat 有助于发展 HIV-SN。因此，在本提案中，我们将进一步研究 Tat 相关的潜在机制。 SN。我们的初步研究确定了 Toll 样受体 (TLR) 信号通路 Tat 的潜在调节作用。 鉴于 TLR 通路参与神经病理性疼痛已被广泛接受，但令人惊讶的是缺乏研究 为了探讨 TLR 通路在 HIV-SN 中的作用，本研究将重点关注 TLR 通路在 Tat 相关 SN 中的作用。 我们将利用生物信息学工具来识别 FDA 批准的药物，而不会产生显着的相互作用 与现有的抗逆转录病毒药物一起使用可能逆转 Tat 诱导的 TLR 通路变化，然后 测试它们在体内治疗 Tat 相关 SN 的有效性。总而言之，我们假设 TLR 信号传导 途径参与 HIV-Tat 相关 SN 的发展，并且有可能识别潜在的 通过结合生物信息学和临床前模型检查现有药物来治疗 HIV-SN 方法。这将通过 2 个具体目标进行测试。目标 1 将决定 Tollip 的贡献（关键 TLR 通路调节器）使用转基因技术调节 HIV Tat 相关 SN 中的 TLR 通路 动物模型与行为和生理测试相结合。目标 2 将确定潜在药物 HIV-SN 通过生物信息学和临床前模型相结合的方法靶向 TLR 通路。如果 如果成功的话，我们将填补有关 Tat 相关 SN 和 TLR 在 HIV-SN 中的作用的知识空白。我们的 全面的组合药物发现策略将有助于识别 HIV-SN 的潜在药物，这可以 在临床评估之前进一步在其他动物模型中进行测试。在整个过程中，我们将优先考虑 候选药物的机制健全，并且可能易于所有患者使用。