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

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，其使用已被认为会加重艾滋病毒相关神经认知障碍（HAND），这是艾滋病最具破坏性的并发症之一。已知滥用药物的HIV-1阳性个体患HIV-脑炎和临床HIV-痴呆的比率较高；HAND的标志。然而，可卡因增强HIV-1在大脑中这些神经效应的能力的详细分子机制仍有待充分了解。我们提出了一种由细胞microRNA“miR-125b”和线粒体代谢酶脯氨酸氧化酶（POX）介导的可卡因和HIV-1诱导的神经元损伤的新机制。这是基于我们的初步数据表明，在可卡因和HIV-1包膜糖蛋白-gp120治疗后，miR-125b在人类神经元（原代和细胞系）中下调。同时，我们还观察到可卡因和gp120处理的神经细胞中肿瘤蛋白53 （p53）的上调。在HIV-1感染的中枢神经系统（CNS）中，p53参与了许多导致神经元损伤的细胞过程。值得注意的是，miR-125b已被证明在神经元细胞中负调控p53。我们的数据还表明，在可卡因和gp120处理的人类原代神经元和神经元细胞模型中，线粒体代谢酶脯氨酸氧化酶（POX）上调。由于POX是由p53诱导的，我们认为POX是miR-125b/p53轴的下游靶点，可能在可卡因和HIV-1诱导的神经元损伤中发挥关键作用。这是因为在脯氨酸催化转化为吡咯-5-羧酸盐（P5C）的过程中，POX会产生活性氧（ROS）。此外，由于P5C是谷氨酸的前体，POX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和上调POX来增强HIV-1相关的神经元损伤。我们认为我们的建议是非常重要的，因为miR-125b和POX在HIV相关神经元损伤中的作用以前没有被描述过。因此，这些研究可能揭示新的机制，并确定新的治疗靶点来消除HAND患者的神经元损伤。我们的假设将通过两个具体目标来检验。目的1：阐明可卡因和HIV-1 gp120诱导的POX上调诱导神经元损伤。目的2：研究miR- 125b是神经细胞中痘的一种新的调节因子。

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.