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: 8484809
• 负责人: Olimpia Meucci
• 金额: $ 31.52万
• 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 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8484809
• 关键词: AIDS neuropathy; 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; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Exhibits; Experimental Models; Ferritin; Goals; HIV; HIV Infections; HIV-1; Human; Image; Immune; Impairment; In Vitro; Individual; Injecting drug user; Iron; Lead; Link; Medical; Molecular; Morphine; Motor; Neurocognitive; 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; neuropathology; non-drug; nonhuman primate; novel; novel therapeutics; 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）：本研究重点关注最近发现的阿片类药物的作用 - 即它们调节神经元中蛋白质铁蛋白重链 (FHC) 的能力 - 及其对 HIV 神经病理学的贡献。该提案的具体目标是：a) 收集阿片类药物使用者 (DU) 大脑中 FHC 变化的证据，并检查 FHC 在 HIV 神经病理学中的潜在作用，b) 阐明参与神经元调节的机制。通过吗啡表达 FHC。本研究的长期目标是进一步探讨HIV/DU患者神经元功能障碍的生物学基础。要测试的一般假设是，鸦片滥用使神经元更容易受到有毒刺激和/或改变其对破坏性侮辱的反应能力，从而加剧艾滋病毒神经病理学。从机制上讲，这可能是由于神经元中 FHC 的异常增加以及随之而来的趋化因子/受体对 CXCL12/CXCR4 的保护作用受损所致。为了测试这些假设，在三个具体目标内提出了强大的技术，即多光谱成像和激光捕获显微切割，以及体外和体内/离体实验方法。目标 1 的研究重点关注 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）中的 FHC 水平。这些研究还有望提供有关 HIV/DU 患者 FHC 变化与神经系统疾病相关性的信息。目标 2 中讨论的实验重点关注吗啡诱导的 FHC 对培养的动物脑组织和皮质神经元中 CXCR4 功能的影响。目标是通过在人类中不可行的对照实验来补充目标 1 研究。这些研究将调查 FHC 对吗啡反应的细胞（即神经元/神经胶质）和亚细胞（细胞质/细胞核）分布，这影响 FHC 与 CXCR4 相互作用和调节 CXCR4 的能力，以及所涉及的机制。最后，目标 3 将解决吗啡和 HIV 对 FHC 作用的分子机制（例如 FHC 的转录后调节和铁蛋白铁结合特性的作用），这是理解该小说的生物学意义的重要一步吗啡在艾滋病毒神经病理学背景下的作用。总体而言，拟议的研究将提供有关 FHC 作为神经元功能和存活调节剂的新作用的重要信息，确定该蛋白质是否是阿片类药物对神经元作用的相关靶标，并描述该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对 FHC 调节作用的机制基础，这项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途径。