HIV and antiretroviral toxic neuropathy

HIV 和抗逆转录病毒毒性神经病

• 批准号: 7338511
• 负责人: Ahmet Hoke
• 金额: $ 41万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7338511
• 关键词: Abbreviations; Adenine Nucleotides; Affect; Animal Model; Anti-Retroviral Agents; Apoptotic; Axon; Binding; Biological Assay; Biological Markers; Cells; Cessation of life; Clinic; Clinical Trials; Complication; Condition; Coupled; Cyclophilins; Data; Development; Dideoxynucleosides; Distal; Erythropoietin; Event; Exposure to; Family; GDNF gene; Genes; Goals; Grant; HIV; HIV Envelope Protein gp120; Heat-Shock Proteins 70; Highly Active Antiretroviral Therapy; Hypoxia Inducible Factor; In Vitro; Incidence; Investigation; Ligands; Mediating; Mitochondria; Modeling; Molecular; Nerve Growth Factor 1; Nerve Growth Factor Pathway; Nerve Growth Factors; Neurologic; Neuronal Dysfunction; Neuropathy; Nitric Oxide Synthase Type I; Outer Mitochondrial Membrane; Oxides; Pain; Pathogenesis; Pathway interactions; Patients; Peptidylprolyl Isomerase; Peripheral Nervous System; Pharmaceutical Preparations; Polyneuropathy; Population; Prevalence; Quality of life; RANTES; Recombinant Erythropoietin; Research Personnel; Role; Schwann Cells; T-Lymphocyte; Testing; Therapeutic; Transgenic Mice; Transgenic Organisms; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Viral Proteins; Virus Diseases; Zalcitabine; base; chemokine receptor; design; env Gene Products; glial cell-line derived neurotrophic factor; human TNF protein; in vitro Model; in vivo Model; injured; major outer membrane protein; mouse model; neuronal cell body; neuroprotection; neurotoxicity; novel; painful neuropathy; prevent; programs; receptor; sensory neuropathy; therapeutic target; treatment effect; vanilloid receptor subtype 1; virus envelope

DESCRIPTION (provided by applicant): Human immunodeficiency virus (HIV) associated sensory neuropathies (H1V-SN) are major neurological complications of the HIV infection and despite the use of highly active antiretroviral therapy (HAART), the incidence and prevalence of this often painful complication of HIV infections remains high. HIV associated sensory neuropathies are often divided into distal symmetric polyneuropathy (DSP) due to the HIV infection per se and antiretroviral toxic neuropathy (ATM) due to the use of dideoxynucleoside (DDX) drugs. Clinically both conditions are similar and likely to have a synergistic role in the pathogenesis of HIV-SN. Currently, there are no therapies aimed at reversing or slowing the progression of these painful neuropathies that affect the quality of life of HIV/AIDS patients. In the previous cycle of this grant, we have developed in vitro models of ATN and DSP and identified a novel endogenous neuroprotective pathway that exist in the peripheral nervous system (PNS). This progress is coupled to the development of a transgenic mouse model of HIV-SN that will be useful in examining the underlying mechanisms of HIV-SN. Furthermore, we identified, erythropoietin as a potential therapeutic target for HIV-SN. In the current application we propose to continue our investigations into the cellular mechanisms of distal axonal degeneration in transgenic mice treated with DDX drugs as well as molecular mechanisms by which HIV proteins and DDX drugs cause neuronal dysfunction and axonal degeneration. We will examine the role of various mitochondrial pathways involved in neuronal dysfunction and death in mediating HIV envelope protein gp120 and DDX neurotoxicity. We will use the animal model of HIV-SN to develop biomarkers of treatment effects in HIV-SN. Finally, we will explore the therapeutic potential of neurotrophic genes regulated by hypoxia inducible factor (HIF), activators of the hsp70 pathway, and cyclophilin ligands to develop novel therapies for HIV-associated sensory neuropathies. These goals are highly relevant to the patient population we serve in the clinic as there are no effective therapies for the painful sensory neuropathy associated with HIV infection and use of DDX drugs.

描述（由申请人提供）：人类免疫缺陷病毒 (HIV) 相关感觉神经病 (H1V-SN) 是 HIV 感染的主要神经系统并发症，尽管使用了高效抗逆转录病毒疗法 (HAART)，但这种常见的令人痛苦的 HIV 感染并发症的发生率和患病率仍然很高。 HIV相关的感觉神经病通常分为由于HIV感染本身引起的远端对称性多发性神经病（DSP）和由于使用双脱氧核苷（DDX）药物引起的抗逆转录病毒中毒性神经病（ATM）。临床上，这两种情况相似，并且可能在 HIV-SN 的发病机制中具有协同作用。目前，尚无旨在逆转或减缓这些影响艾滋病毒/艾滋病患者生活质量的痛苦神经病进展的疗法。在本次资助的上一周期中，我们开发了 ATN 和 DSP 的体外模型，并确定了周围神经系统 (PNS) 中存在的一种新型内源性神经保护途径。这一进展与 HIV-SN 转基因小鼠模型的开发相结合，该模型将有助于检查 HIV-SN 的潜在机制。此外，我们确定促红细胞生成素是 HIV-SN 的潜在治疗靶点。在当前的申请中，我们建议继续研究用DDX药物治疗的转基因小鼠远端轴突变性的细胞机制，以及HIV蛋白和DDX药物导致神经元功能障碍和轴突变性的分子机制。我们将研究涉及神经元功能障碍和死亡的各种线粒体途径在介导 HIV 包膜蛋白 gp120 和 DDX 神经毒性中的作用。我们将使用 HIV-SN 动物模型来开发 HIV-SN 治疗效果的生物标志物。最后，我们将探索由缺氧诱导因子 (HIF)、hsp70 通路激活剂和亲环蛋白配体调节的神经营养基因的治疗潜力，以开发治疗 HIV 相关感觉神经病的新疗法。这些目标与我们在诊所服务的患者群体高度相关，因为对于与 HIV 感染和使用 DDX 药物相关的疼痛性感觉神经病，尚无有效的治疗方法。