Role of PERK haplotypes in HIV-Associated Neurocognitive Disorders

PERK 单倍型在 HIV 相关神经认知障碍中的作用

• 批准号: 9317357
• 负责人: Kelly L Jordan-Sciutto
• 金额: $ 54.84万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-16 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9317357
• 关键词: ATF6 gene; Ablation; Adult; Affect; Age; Aging; Alzheimer' s Disease; Amyloid beta-Protein Precursor; Anti-Retroviral Agents; Attenuated; Autopsy; Behavioral; Binding; Binding Proteins; Biological Markers; Brain; CD4 Lymphocyte Count; Chronic; Cleaved cell; Clinical; Code; Cognitive; Cognitive deficits; Collaborations; Comorbidity; Complex; Data; Development; Diagnosis; Disease; Drug abuse; Early Intervention; Enzymes; Eukaryotic Initiation Factors; Exhibits; Frequencies; General Population; Genes; Genetic; Genetic Markers; Gliosis; HIV; HIV Envelope Protein gp120; HIV Protease Inhibitors; HIV Seropositivity; HIV antiretroviral; HIV-associated neurocognitive disorder; Haplotypes; Health; Hepatitis C co-infection; Human; In Vitro; Individual; Life Expectancy; Link; Mediating; Mental Depression; Metabolic syndrome; Mind; Molecular; Molecular Chaperones; Mus; Nerve Degeneration; Neurocognitive; Neurodegenerative Disorders; Neuronal Injury; Neurons; Outcome; Oxidative Stress; Parkinson Disease; Pathologic; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Phosphorylation; Phosphotransferases; Prefrontal Cortex; Process; Progressive Supranuclear Palsy; Protease Inhibitor; Proteins; Risk; Risk Factors; Rodent; Rodent Model; Role; Single Nucleotide Polymorphism; Site; Synapses; Therapeutic; Time; Toxic effect; Transgenic Mice; Translations; Viral; Virus Replication; age related; amyloid precursor protein processing; antiretroviral therapy; arm; astrogliosis; base; beta-site APP cleaving enzyme 1; brain tissue; cohort; disorder risk; effective therapy; genetic risk factor; genetic variant; genome wide association study; improved; in vitro Model; in vivo; in vivo Model; inhibitor/antagonist; macrophage; neuron loss; neuropathology; neuroprotection; neurotoxicity; outcome forecast; pre-clinical; precision medicine; predictive marker; programs; protein function; response; stressor; success

HIV-Associated Neurocognitive Disorder (HAND) continues to affect ~50% of HIV(+) patients despite widespread implementation of antiretroviral therapy (ART) and successful viral suppression. Several risk factors including older age, low nadir CD4+ cell count, metabolic syndrome, depression and hepatitis C co-infection associate with HAND. Early interventions and complete viral suppression are most likely to improve neurocognitive (NC) prognosis; the Mind Exchange Program recommends consideration of risk factors for diagnosis and treatment within the first six months. Many of the mechanisms implicated in HAND persistence, including unremitting CNS viral replication, age-related pathologies, comorbidities (e.g., drug abuse, ART-associated toxicities) can induce the unfolded protein response (UPR), which results in activation of one or more of the 3 initiators, PERK, ATF6, and IRE1α, when cellular stressors disrupt their binding to the chaperone, binding protein (BiP), with wide ranging consequences. Most pertinent here is PERK-mediated phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) slows global translation, while selectively enhancing translation of a subset of genes including the beta-site amyloid precursor protein cleaving enzyme 1 (BACE1). Chronic and/or sustained UPR activation may have detrimental outcomes, supported by multiple studies. Consistently, UPR is implicated in several neurodegenerative diseases, including Alzheimer and Parkinson. We previously showed UPR activation in HAND prefrontal cortex. Based on multiple lines of evidence from in vitro and in vivo models of HIV-induced neurodegeneration, suggesting that the dysregulation of the PERK arm of the UPR pathway may be contributing to HIV- as well as antiretroviral-mediated neurodegenerative processes, we propose a role for PERK dysregulation as a mechanism for the continuing neuronal perturbations still observed in HAND patients despite ART’s success. We propose that PERK activation contributes to HAND development, and a genetic variant of PERK with increased activity is a predictive risk factor for HAND. In this application, we will examine whether a protein-coding PERK haplotype resulting from three single nucleotide polymorphisms (SNPs), which may confer increased kinase activity, may underlie the alteration/s of PERK’s protein function and/or changes in its amount. We will determine: 1) the mechanisms of PERK-mediated neurotoxicity in vitro, 2) the mechanisms of PERK-mediated neuronal injury in a preclinical rodent model of HIV-induced synaptic damage, gliosis and behavioral/cognitive deficits, and 3) the associations between PERK genetic haplotype and/or expression with HAND risk in human adults.

尽管 HIV 相关神经认知障碍 (HAND) 广泛存在，但它仍继续影响约 50% 的 HIV(+) 患者 实施抗逆转录病毒治疗（ART）并成功抑制病毒。几个风险因素包括 年龄较大、最低 CD4+ 细胞计数低、代谢综合征、抑郁症和丙型肝炎合并感染与 手。早期干预和完全病毒抑制最有可能改善神经认知（NC） 预后；心灵交流计划建议诊断和治疗时考虑风险因素 前六个月内。许多与 HAND 持久性有关的机制，包括不间断的 CNS 病毒复制、与年龄相关的病理、合并症（例如药物滥用、ART 相关毒性）可诱发 未折叠蛋白反应 (UPR)，导致 3 个启动子 PERK、ATF6 中的一个或多个激活， 和 IRE1α，当细胞应激源破坏其与分子伴侣结合蛋白 (BiP) 的结合时， 范围广泛的后果。这里最相关的是 PERK 介导的真核翻译起始磷酸化 因子 2α (eIF2α) 会减慢全局翻译，同时选择性地增强基因子集的翻译，包括 β 位点淀粉样蛋白前体蛋白裂解酶 1 (BACE1)。慢性和/或持续的UPR激活 可能会产生有害的结果，并得到多项研究的支持。一致地，普遍定期审议与若干事件有关 神经退行性疾病，包括阿尔茨海默病和帕金森病。我们之前展示了 UPR 激活 手前额皮质。基于来自 HIV 诱导的体外和体内模型的多项证据 神经退行性变，表明 UPR 通路 PERK 臂的失调可能是导致 对于 HIV 以及抗逆转录病毒介导的神经退行性过程，我们提出 PERK 的作用 尽管在 HAND 患者中仍然观察到调节失调作为持续神经元扰动的机制 艺术的成功。我们认为 PERK 激活有助于 HAND 发育，并且遗传变异 PERK 的活性增加是 HAND 的预测危险因素。在此应用程序中，我们将检查 蛋白质编码 PERK 单倍型是否由三个单核苷酸多态性 (SNP) 产生， 可能会增加激酶活性，可能是 PERK 蛋白质功能改变和/或 它的数量。我们将确定：1）PERK 介导的体外神经毒性机制，2）机制 在 HIV 诱导的突触损伤、神经胶质增生和神经胶质增生的临床前啮齿动物模型中，PERK 介导的神经元损伤的研究 行为/认知缺陷，以及 3) PERK 遗传单倍型和/或表达与 成人的手部风险。