Effects of opiates on neurons and their impact on HIV neuropathology

阿片类药物对神经元的影响及其对 HIV 神经病理学的影响

• 批准号: 9100679
• 负责人: Olimpia Meucci
• 金额: $ 32.5万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9100679
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adherence; Adopted; Affect; Agonist; Animal Model; Animals; Anti-Retroviral Agents; Autopsy; Binding; Biological; Brain; CXCL12 gene; CXCR4 gene; Cell Nucleus; Cells; Complement; Complex; Cytosol; Development; Disease; Drug abuse; Drug user; Exhibits; Experimental Models; Ferritin; Goals; HIV; HIV Infections; HIV-1; HIV-associated neurocognitive disorder; Human; Image; Immune; Impairment; In Vitro; Individual; Injecting drug user; Iron; Lead; Link; Medical; Molecular; Morphine; Motor; Neurocognitive; Neurocognitive Deficit; Neuroglia; Neurologic; Neuronal Dysfunction; Neurons; Opiates; Opioid; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Prefrontal Cortex; Property; Proteins; Recording of previous events; Regulation; Research; Rodent; Role; Sensory; Signal Transduction; Stimulus; Techniques; Testing; Therapeutic Intervention; Time; Tissues; Transcript; Transcriptional Regulation; Up-Regulation; Viral Proteins; antiretroviral therapy; base; brain tissue; chemokine receptor; clinically relevant; drug abuser; in vivo; innovation; insight; laser capture microdissection; nervous system disorder; neuroAIDS; neuropathology; non-drug; nonhuman primate; novel; novel therapeutic intervention; opioid abuse; prevent; research study; response; social

DESCRIPTION (provided by applicant): This research focuses on a recently discovered effect of opiates - i.e. their ability to regulate the protein ferritin heavy chain (FHC) in neurons - andits contribution to HIV neuropathology. The specific objectives of this proposal are: a) to collect evidence of FHC changes in the brain of opiate drug users (DU) and examine the potential role of FHC in HIV neuropathology, and b) to elucidate the mechanisms involved in the regulation of neuronal FHC expression by morphine. The long-term goal of this research is to further explore the biological basis of neuronal dysfunction in HIV/DU patients. The general hypothesis to be tested is that opiate abuse exacerbates HIV neuropathology by rendering neurons more vulnerable to toxic stimuli and/or by altering their ability of responding to damaging insults. Mechanistically, this could be caused by abnormal increase of FHC in neurons and consequent impairment of the protective actions of the chemokine/receptor pair CXCL12/CXCR4. To test these hypotheses powerful techniques, i.e. Multispectral Imaging and Laser Capture Microdissection, along with in vitro and in vivo/ex vivo experimental approaches are proposed, within three specific aims. Studies in aim 1 focus on the expression of FHC in autopsy brain tissue from HIV/DU patients - with the primary intent of establishing whether drug abuse alters FHC levels in the human brain, mainly in cortical neurons. These studies are also expected to provide information about the correlation of FHC changes with neurological disorders in HIV/DU patients. The experiments discussed in aim 2 focuses on the consequences of morphine-induced FHC on CXCR4 function in animal brain tissue and cortical neurons in culture. The goal is to complement aim 1 studies with controlled experiments that are not feasible in humans. These studies will investigate the cellular (i.e. neurons/glia) and subcellular (cytosol /nucleus) distribution of FHC in response to morphine, which influence FHC ability to interact with and modulate CXCR4, and the mechanisms involved. Finally, aim 3 will tackle the molecular mechanisms involved in the action of morphine and HIV on FHC (such as posttranscriptional regulation of FHC and the role of ferritin iron binding properties), which is an important step toward understanding of the biological implications of this novel action of morphine in the context of HIV neuropathology. Overall, the proposed research will provide essential information about a novel role of FHC as a regulator of neuronal function and survival, determine if this protein is a relevant target of opiate action on neurons, and characterize both the consequences of this action and some of the mechanisms involved in neuropathology. By characterizing the role of FHC in neuronal dysfunction and identifying the mechanistic basis of opiates action on FHC regulation, this research will provide new avenues for therapeutic intervention aimed at preventing or reducing the neurological complications of HIV infection.

描述（由申请人提供）：本研究的重点是最近发现的阿片类药物的作用-即它们调节神经元中铁蛋白重链（FHC）的能力-及其对HIV神经病理学的贡献。本提案的具体目标是：a)收集阿片类药物使用者（DU）大脑中FHC变化的证据，并研究FHC在HIV神经病理学中的潜在作用；b)阐明吗啡调节神经元FHC表达的机制。本研究的长期目标是进一步探索HIV/DU患者神经元功能障碍的生物学基础。需要验证的一般假设是，阿片类药物滥用通过使神经元更容易受到有毒刺激和/或改变其对破坏性损伤的反应能力，加剧了HIV神经病理学。从机制上说，这可能是由于神经元中FHC的异常增加和趋化因子/受体对CXCL12/CXCR4的保护作用随之受损所致。为了验证这些假设，在三个特定目标下，提出了强大的技术，即多光谱成像和激光捕获显微解剖，以及体外和体内/离体实验方法。目的1的研究集中在HIV/DU患者尸检脑组织中FHC的表达，主要目的是确定药物滥用是否会改变人脑（主要是皮质神经元）中FHC的水平。这些研究还有望提供关于FHC变化与HIV/DU患者神经系统疾病相关性的信息。目的2中讨论的实验主要关注吗啡诱导的FHC对培养动物脑组织和皮质神经元中CXCR4功能的影响。目标是用在人类身上不可行的对照实验来补充目标1的研究。这些研究将探讨吗啡对FHC的细胞（即神经元/神经胶质）和亚细胞（细胞质/细胞核）分布的影响，FHC与CXCR4相互作用和调节的能力，以及相关机制。最后，目的3将解决涉及吗啡和HIV对FHC作用的分子机制（如FHC的转录后调控和铁蛋白铁结合特性的作用），这是理解吗啡在HIV神经病理学背景下这种新作用的生物学意义的重要一步。总的来说，拟议的研究将提供关于FHC作为神经元功能和存活调节剂的新作用的基本信息，确定该蛋白是否是阿片作用于神经元的相关靶点，并描述这种作用的后果和一些涉及神经病理学的机制。通过表征FHC在神经元功能障碍中的作用，并确定阿片类药物作用于FHC调节的机制基础，本研究将为旨在预防或减少HIV感染神经系统并发症的治疗干预提供新的途径。