Glial versus Neuronal Caspase-3 in Opioid-HIV gp120 Neurotoxicity

阿片类药物-HIV gp120 神经毒性中的胶质细胞与神经元 Caspase-3

• 批准号: 8263482
• 负责人: Kimberly Lynne Samano
• 金额: $ 4.04万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-25 至 2014-05-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8263482
• 关键词: AIDS Dementia Complex; Acquired Immunodeficiency Syndrome; Affect; Alzheimer' s Disease; Antibodies; Apoptosis; Apoptotic; Astrocytes; Attenuated; BIRC4 gene; Basal Ganglia; Behavior; CCL2 gene; Caspase; Cell Death; Cell Survival; Cells; Cellular Stress; Cessation of life; Cleaved cell; Coculture Techniques; Cognitive; Comorbidity; Corpus striatum structure; Dementia; Disease; Encephalitis; Epidemic; Flow Cytometry; Functional disorder; Gelsolin; Glial Fibrillary Acidic Protein; Gliosis; Glycoproteins; Goals; HIV; HIV Envelope Protein gp120; HIV Seropositivity; HIV-1; Health; Heroin; Human; Image; Immunohistochemistry; In Situ Nick-End Labeling; In Vitro; Individual; Infection; Inflammation; Injectable; Injection of therapeutic agent; Interleukin-1; Knock-out; Knockout Mice; Lead; Life; Mediating; Membrane; Microglia; Microscopy; Mitochondria; Morphine; Motor; Mus; Naltrexone; Nature; Neurocognitive; Neurodegenerative Disorders; Neuroglia; Neurologic; Neuronal Injury; Neurons; Neuropathogenesis; Neurotoxins; Opioid; Opioid Receptor; Optics; Paper; Parkinson Disease; Pathogenesis; Patients; Pharmaceutical Preparations; Play; Prevention; Publishing; RANTES; Reagent; Receptor Signaling; Research; Rodent Model; Role; Syndrome; System; TNF gene; Testing; Therapeutic; Therapeutic Agents; Toxic Actions; Toxic effect; Training; Viral; Viral Load result; Western Blotting; antiretroviral therapy; caspase-3; cell type; design; digital; drug abuser; extracellular; genome-wide; immune function; in vivo; interest; mu opioid receptors; neuron apoptosis; neurotoxicity; novel; opioid abuse; pre-doctoral; psychologic; receptor expression; research study; response; time use

DESCRIPTION (provided by applicant): HIV-1 is a global epidemic spread predominantly through sexual contact and through the use of injectable drugs, such as heroin. Since the implementation of cART (Combined Active Antiretroviral Therapy) in the mid 1990's, infected individuals are living longer with HIV-1 and AIDS, which augments the neurological and psychological profiles associated with HIV-1. Collectively, these CNS deficits are known as HIV-1 associated neurocognitive disorders (HAND) and include HIV-associated dementia (HAD) and HIV-associated encephalitis (HIVE). Broadly, HAND syndromes are characterized by cognitive, motor and behavior dysfunctions; indicative of basal ganglia dysfunction [7,34,42,75]. In conjunction with high viral load in patients, the striatal region within the basal ganglia preferentially has a high abundance of mu- opioid receptor (MOR) expression [24]. Opioids are known to modulate immune function and this confound is likely to worsen the pathogenesis and neurological complications of HIV-1 [20,44-6,66,74]. The viral coat glycoprotein of HIV-1, gp120, is an established neurotoxin that is required for viral entry and infection, and its extracellular actions are toxic to neurons and glia (microglia and astrocytes) in vitro and in vivo in both human and rodent models [4,5,9,11,12,15,17,19,35,50,51, 60,61,70]. Our lab and others have demonstrated how opioids potentiate this gp120 induced neurotoxicity [1,28,45]. We have shown that gp120 increases caspase-3 activity and induces apoptosis of striatal neurons. We are interested in better understanding how opioids affect HIV-gp120 induced neurotoxicity within the striatum and specifically want to investigate the role of caspase-3 in both glial and neuronal mediated mechanisms of neurotoxicity. Studies are proposed to determine if glial caspase-3 mediates gp120 neurotoxicity 1 opioids, and to establish whether opioids act via caspase-3 to directly affect neuron injury and/or death in vitro using caspase-3 knockout cells. Finally, we wil employ the use of caspase-3 knockout mice to investigate how genome-wide deletion of the executioner caspase will affect glial and neuronal responses after gp120 1 opioids in vivo. Collectively, the proposed studies will add to the understanding of how caspase-3 plays a role in the interactive co-morbidity of gp120 and opioids in regards to HIV neuropathogenesis. With this information, a better understanding of underlying mechanisms are made possible which lead to new options in therapeutics, which have ramifications for opioid abusers and users infected with HIV-1. PUBLIC HEALTH RELEVANCE: HIV-positive opioid drug abusers show an expedited progression to AIDS and since infected individuals are living longer with current antiretroviral therapy there is an increasing rate of HIV-associated neurocognitive disorders including dementia. Our research will help identify potential therapeutic agents for the prevention and treatment of neurocognitive dysfunction in HIV-positive individuals using and/or abusing opioids.

描述（由申请人提供）：HIV-1是一种全球流行病，主要是通过性接触和使用可注射药物（例如海洛因）。自1990年代中期实施购物车（合并活跃的抗逆转录病毒疗法）以来，受感染的个体使用HIV-1和艾滋病的寿命更长，这增加了与HIV-1相关的神经和心理特征。总的来说，这些中枢神经系统缺陷被称为HIV-1相关的神经认知疾病（手），包括与HIV相关的痴呆症（HAD）和与HIV相关的脑炎（HIVE）。从广义上讲，手动综合征的特征是认知，运动和行为功能障碍。指示基底神经节功能障碍[7,34,42,75]。结合患者的高病毒载量，基底神经节内的纹状体区域优先具有高丰度的混血受体（MOR）表达[24]。已知阿片类药物可以调节免疫功能，这种混杂可能会使HIV-1的发病机理和神经系统并发症恶化[20,44-6,666,74]。 HIV-1，GP120的病毒外套糖蛋白是一种已建立的神经毒素，它是病毒入口和感染所必需的，其细胞外作用对神经元和神经元和神经胶质（小胶质细胞和星形胶质细胞）有毒 在人类和啮齿动物模型中[4,5,9,11,12,15,17,19,35,50,51，60,61,70]。我们的实验室和其他实验室已经证明了阿片类药物如何增强这种GP120诱导神经毒性[1,28,45]。我们已经表明，GP120增加了caspase-3活性并诱导纹状体神经元的凋亡。我们有兴趣更好地了解阿片类药物如何影响纹状体内HIV-GP120诱导的神经毒性，并特别希望研究Caspase-3在神经毒性和神经元介导的神经毒性机制中的作用。提出了研究以确定Glial Caspase-3是否介导GP120神经毒性1阿片类药物，并确定阿片类药物是否通过caspase-3作用于直接影响神经元损伤和/或使用caspase-3敲除细胞在体外影响神经元损伤和/或死亡。最后，我们将利用使用caspase-3基因敲除小鼠来研究execution子caspase的全基因组缺失如何影响gp120 1 gp120 1阿片类药物在体内的神经胶质和神经元反应。总的来说，拟议的研究将增加对Caspase-3如何在GP120和阿片类药物的互动性合并症中发挥作用的理解。有了这些信息，可以更好地理解基本机制，从而导致治疗方法的新选择，这对阿片类药物滥用者和感染了HIV-1的用户产生了影响。 公共卫生相关性：HIV阳性阿片类药物滥用者表明，加快艾滋病的进展，并且由于感染的个体使用当前的抗逆转录病毒疗法的寿命更长，因此艾滋病毒相关的神经认知疾病的发生率越来越高。我们的研究将有助于确定使用和/或滥用阿片类药物的HIV阳性个体中神经认知功能障碍预防和治疗神经认知功能障碍的潜在治疗剂。