Mir-125b/p53/POX axis and HIV-1 induced neurological damage

Mir-125b/p53/POX 轴和 HIV-1 诱导的神经损伤

• 批准号: 8927599
• 负责人: Jui Pandhare
• 金额: $ 14.33万
• 依托单位: MEHARRY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8927599
• 关键词: AIDS Dementia Complex; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Address; Affect; Apoptotic; Area; Award; Binding; Biochemistry; Brain; Cell Line; Cell model; Cell physiology; Cells; Clinical; Cocaine; Cocaine Abuse; Cocaine Users; Data; Dementia; Down-Regulation; Drug abuse; Drug usage; Effectiveness; Encephalitis; Enzymes; Genes; Glutamates; Glycoproteins; Goals; HIV; HIV Envelope Protein gp120; HIV Seropositivity; HIV encephalitis; HIV-1; HIV-associated neurocognitive disorder; Human; Individual; Injury; Journals; Measures; Mediating; Metabolic; Metabolism; MicroRNAs; Minor; Mitochondria; Molecular; National Institute of Drug Abuse; Nervous System Trauma; Neuraxis; Neurologic; Neurons; Pathogenesis; Patients; Peer Review; Pharmaceutical Preparations; Play; Prevalence; Production; Proline; Proline Dehydrogenase; Proteins; Publishing; Reactive Oxygen Species; Research; Research Personnel; Role; Small Interfering RNA; Symptoms; Synapses; Testing; Time; Up-Regulation; antiretroviral therapy; base; carboxylate; excitotoxicity; innovation; knock-down; mitochondrial membrane; motor disorder; new therapeutic target; novel; overexpression; programs; public health relevance; pyrroline; tumor

DESCRIPTION (provided by applicant): Cocaine is a commonly used drug among HIV-infected individuals, and its use has been suggested to worsen HIV-associated neurocognitive disorders (HAND), one of the most devastating complications of AIDS. Drug-abusing HIV-1-positive individuals are known to have higher rates of HIV-encephalitis and clinical HIV dementia; the hallmarks of HAND. However, the detailed molecular mechanisms underlying the ability of cocaine to enhance these neurological effects of HIV-1 in the brain still remains to be fully understood. We propose a novel mechanism mediated by the cellular microRNA "miR-125b" and the mitochondrial metabolic enzyme Proline oxidase (POX) in cocaine and HIV-1 induced neuronal damage. This is based on our preliminary data that demonstrate downregulation of miR-125b in human neurons (both primary and cell lines) upon treatment with cocaine and HIV-1 envelop glycoprotein-gp120. Concurrently, we also observed upregulation of the tumor protein 53 (p53) in cocaine and gp120 treated neuronal cells. p53 has been implicated in many cellular processes leading to neuronal damage in the HIV-1 infected central nervous system (CNS). Notably, miR-125b has been demonstrated to negatively regulate p53 in neuronal cells. Our data also illustrate upregulation of the mitochondrial metabolic enzyme Proline Oxidase (POX) in cocaine and gp120 treated human primary neurons and neuronal cell models. Since POX is induced by p53, we propose that POX is a downstream target of the miR-125b/p53 axis that may play a critical role in cocaine and HIV-1 induced neuronal damage. This is because POX generates reactive oxygen species (ROS) during the catalytic conversion of proline to pyrroline-5-carboxylate (P5C). Additionally, upregulation of POX can increase glutamate levels since P5C is a precursor of glutamate. Given that increased levels of ROS and glutamate are implicated in neuronal damage, we hypothesize that cocaine enhances HIV-1 associated neuronal damage by downregulating miR-125b and upregulating POX. We believe our proposal is highly significant since the roles of miR-125b and POX in HIV associated neuronal damage have not been previously described. Therefore, these studies may uncover a novel mechanism and identify new therapeutic targets for abrogating neuronal damage in HAND patients. Our hypothesis will be tested through two specific aims. Aim 1: Elucidate that cocaine and HIV-1 gp120 induced upregulation of POX induces neuronal damage. Aim 2: Examine that miR- 125b is a novel regulator of POX in neuronal cells.

描述（由申请人提供）：可卡因是艾滋病毒感染者中常用的药物，并建议其使用来恶化与HIV相关的神经认知障碍（Hand），这是艾滋病中最具破坏性的并发症之一。众所周知，滥用药物的HIV-1阳性个体具有更高的HIV-脑炎和临床HIV痴呆症。手的标志。但是，可卡因增强HIV-1在大脑中这些神经系统作用的能力的详细分子机制仍然有待充分理解。我们提出了一种由可卡因和HIV-1中的细胞MicroRNA“ miR-125b”和线粒体代谢酶脯氨酸氧化酶（POX）介导的新型机制。这是基于我们的初步数据，该数据表明可卡因和HIV-1包膜糖蛋白GP120治疗后，人神经元（原发性和细胞系）中miR-125b的下调。同时，我们还观察到可卡因和GP120治疗的神经元细胞中肿瘤蛋白53（p53）的上调。 p53与许多细胞过程有关，导致HIV-1感染中枢神经系统（CNS）的神经元损伤。值得注意的是，已证明miR-125b在神经元细胞中对p53进行负调控。我们的数据还说明了可卡因和GP120治疗的人类原发性神经元和神经元细胞模型中线粒体代谢酶氧化酶（POX）的上调。由于POX是由p53诱导的，因此我们建议POX是miR-125b/p53轴的下游靶标，它可能在可卡因和HIV-1诱导的神经元损伤中起关键作用。这是因为在脯氨酸催化转化为吡咯氨酸-5-羧酸盐（P5C）期间，POX会产生活性氧（ROS）。另外，由于P5C是谷氨酸的前体，因此痘痘的上调可以增加谷氨酸水平。鉴于ROS和谷氨酸水平的升高与神经元损伤有关，我们假设可卡因通过下调miR-125b并上调POX来增强HIV-1相关的神经元损伤。我们认为我们的建议非常重要，因为MiR-125b和Pox在HIV相关的神经元损伤中的作用尚未描述。因此，这些研究可能会发现一种新型的机制，并确定了废除手动患者神经元损害的新治疗靶标。我们的假设将通过两个具体目标进行检验。 AIM 1：阐明可卡因和HIV-1 GP120诱导痘痘的上调会诱导神经元损伤。目标2：检查miR-125b是神经元细胞中痘痘的新调节剂。