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.

HIV相关的神经认知障碍（HAND）继续影响约50%的HIV（+）患者，尽管广泛的 实施抗逆转录病毒治疗（ART）和成功的病毒抑制。一些风险因素包括 年龄较大，CD 4+细胞计数最低值低，代谢综合征，抑郁症和丙型肝炎合并感染与 手早期干预和完全抑制病毒最有可能改善神经认知（NC） 预后;精神交流计划建议考虑诊断和治疗的风险因素 在头六个月内。HAND持续存在的许多机制，包括持续的CNS 病毒复制，年龄相关的病理，合并症（例如，药物滥用、ART相关毒性）可诱导 未折叠蛋白反应（UPR），其导致3种起始物，PERK，ATF 6， 和IRE 1 α，当细胞应激物破坏它们与伴侣蛋白结合蛋白（BiP）的结合时， 后果的范围。这里最相关的是PERK介导的真核翻译起始的磷酸化 因子2α（eIF 2 α）减缓了整体翻译，同时选择性地增强了一部分基因的翻译，包括 β位点淀粉样前体蛋白裂解酶1（BACE 1）。慢性和/或持续的UPR激活 可能会产生有害的结果，这得到了多项研究的支持。因此，普遍定期审议涉及到若干问题， 神经退行性疾病，包括阿尔茨海默病和帕金森病。我们之前显示UPR激活在 手前额叶皮层。基于来自HIV诱导的体外和体内模型的多条证据， 这表明UPR通路的PERK臂的失调可能是导致神经变性的原因。 对于HIV和抗逆转录病毒介导的神经退行性过程，我们提出PERK的作用 调节异常作为持续神经元扰动的机制仍然在HAND患者中观察到， 艺术的成功。我们认为PERK激活有助于HAND的发育， 活动增加的PERK是HAND的预测风险因素。在这个应用程序中，我们将检查 是否由三个单核苷酸多态性（SNP）引起的蛋白质编码PERK单倍型， 可能赋予激酶活性增加，可能是PERK蛋白功能改变和/或 其金额。我们将确定：1）PERK介导的体外神经毒性机制，2） PERK介导的神经元损伤在HIV诱导的突触损伤、神经胶质增生和 行为/认知缺陷，和3）PERK基因单倍型和/或表达与 成年人的手风险。