HIV and antiretroviral toxic neuropathy

HIV 和抗逆转录病毒毒性神经病

基本信息

批准号：
8109855
负责人：
Ahmet Hoke
金额：
$ 40.18万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-09-30 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8109855
关键词：
Abbreviations Acquired Immunodeficiency Syndrome Adenine Nucleotides Affect Animal Model Anti-Retroviral Agents Apoptotic Axon Binding Biological Assay Biological Markers Cells Cessation of life Clinic Clinical Trials Complication 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 Factors Neurologic Neuronal Dysfunction Neuropathy Nitric Oxide Synthase Type I Outer Mitochondrial Membrane Oxides Pain Pathogenesis Pathway interactions Patients Peripheral Nervous System Pharmaceutical Preparations Polyneuropathy Prevalence Quality of life RANTES Recombinant Erythropoietin Research Personnel Role Schwann Cells Stromal Cell-Derived Factor 1 T-Lymphocyte TNF gene Testing Therapeutic Transgenic Mice Tumor Necrosis Factor-alpha Viral Proteins Virus Diseases axonal degeneration base chemokine receptor design effective therapy env Gene Products glial cell-line derived neurotrophic factor in vitro Model in vivo Model injured major outer membrane protein mouse model neuronal cell body neuroprotection neurotoxicity novel painful neuropathy patient population prevent programs receptor sensory neuropathy therapeutic target therapy development treatment effect vanilloid receptor subtype 1 virus envelope

项目摘要

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）相关的感觉神经病（H1V-SN）是HIV感染的主要神经系统并发症，尽管使用了高度活跃的抗逆转录病毒疗法（HAART），但这种经常痛苦的艾滋病毒感染的发生率和患病率仍然很高。 HIV相关的感觉神经病通常由于使用二羟基核苷（DDX）药物而导致的HIV感染本身和抗逆转录病毒毒性神经病（ATM），通常分为远端对称多神经病（DSP）。临床上这两种情况都相似，并且在HIV-SN的发病机理中可能具有协同作用。目前，尚无旨在逆转或减缓影响艾滋病毒/艾滋病患者生活质量的疗法。在该赠款的上一个周期中，我们开发了ATN和DSP的体外模型，并确定了周围神经系统（PNS）中存在的新型内源性神经保护途径。此进展与HIV-SN的转基因小鼠模型的开发相结合，该模型将在检查HIV-SN的基本机制中有用。此外，我们确定促红细胞生成素是HIV-SN的潜在治疗靶点。在当前的应用中，我们建议继续研究用DDX药物处理的转基因小鼠远端轴突变性的细胞机制，以及HIV蛋白和DDX药物引起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中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的动物模型来发展HIV-SN治疗效应的生物标志物。最后，我们将探索由缺氧诱导因子（HIF）调节的神经营养基因的治疗潜力，HSP70途径的激活剂和环粒蛋白配体开发用于HIV相关感觉神经病的新型治疗方法。这些目标与我们在诊所服务的患者人群高度相关，因为没有有效的疗法来治疗与HIV感染和DDX药物使用相关的疼痛感觉神经病。