Iron and Mitochondrial Genomics in Neuro-inflammation and HAND: A CHARTER Study

描述(由申请人提供)：HIV-1相关神经认知障碍(HAND)仍然普遍存在，并且对HIV感染的并发症知之甚少，影响死亡率，即使在通过联合抗逆转录病毒疗法(CART)有效抑制病毒的个人中也会发生。HAND在HIV感染者中表达的广泛差异表明宿主基因组在其发病机制中存在差异；HIV疾病进展、神经炎症和CART的线粒体效应的相对贡献尚不清楚。线粒体功能异常会影响模型系统中的神经退化过程，在人类神经认知障碍中很常见。中枢神经系统(CNS)中铁的调节运输对于线粒体的正常功能如氧化磷酸化(OXPHOS)和控制性细胞死亡是至关重要的；最近的研究也揭示了铁运输和炎症之间的密切联系。对核DNA(NDNA)和不同的线粒体DNA(MtDNA)基因组中影响铁代谢和线粒体OXPHOS的变异进行协调研究，可能会显著促进对复杂神经认知障碍(如手)的理解。作为与CNS HIV抗逆转录病毒治疗效应研究(CHECH)研究小组持续合作的一部分，我们的研究团队领导了了解铁相关nDNA基因和mtDNA变异在CART相关并发症(包括周围神经病变)中的作用。基于我们的发现和迄今的文献，我们假设影响铁运输和线粒体OXPHOS的nDNA和mtDNA变体独立地和联合地影响与手相关的中间表型，例如脑脊液(CSF)中铁相关蛋白的水平、mtDNA拷贝数和基因组DNA甲基化模式(包括炎症和铁相关基因的甲基化)，例如脑脊液(CSF)中的炎症生物标记物水平、血脑屏障中的铁运输。这一高度协作的提案建立在几个研究团队的多学科专业知识、联合初步数据和特殊的宪章研究资源的基础上。重要的是，它将通过创建一个丰富的双基因组(nDNA和mtDNA)数据库来利用Charge中现有的NIH资助的项目，该数据库与血液和脑脊液(CSF)生物标记物数据以及1000名受试者的细致神经认知评估相关联。我们将使用最先进的和新颖的计算方法通过三个具体目标来表征手的基因组调节：1)确定与铁相关的nDNA和mtDNA变体对脑脊液中神经炎性生物标记物水平的影响；2)确定nDNA和mtDNA变体对脑脊液中铁相关蛋白谱和单核细胞mtDNA拷贝数的影响；以及3)确定与nDNA(铁相关)和mtDNA基因组调节脑脊液中间表型有关的手的易感性的比例。

DESCRIPTION (provided by applicant): HIV-1-Associated Neurocognitive Disorders (HAND) remain prevalent and poorly understood complications of HIV infection, impacting mortality and occurring even in individuals with effective viral suppression by combination antiretroviral therapy (cART). Wide variation in the expression of HAND in HIV-infected individuals implicates host genomic variation in its pathogenesis; the relative contributions of HIV disease progression, neuroinflammation, and the mitochondrial effects of cART are unknown. Abnormal mitochondrial function influences neurodegenerative processes in model systems and is common in human neurocognitive disorders. Regulated iron transport in the central nervous system (CNS), which is incompletely understood, is vital for normal mitochondrial functions like oxidative phosphorylation (OXPHOS) and control of programmed cell death; recent research also reveals intimate links between iron transport and inflammation. Coordinated studies of variants in nuclear DNA (nDNA) and the distinct mitochondrial DNA (mtDNA) genome that influence iron metabolism and mitochondrial OXPHOS may significantly advance understanding of complex neurocognitive disorders such as HAND. Our research team has led efforts to understand the role of variation in both iron-related nDNA genes and mtDNA in cART-associated complications, including peripheral neuropathy, as part of ongoing collaborations with the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) Study group. Based on our findings and the literature to date, we hypothesize that nDNA and mtDNA variants that impact iron transport and mitochondrial OXPHOS independently and jointly influence intermediate HAND-associated phenotypes, such as inflammation biomarker levels in CSF, iron transport across the blood-brain barrier as evidenced by levels of iron-related proteins in cerebrospinal fluid (CSF), mtDNA copy number, and genomic DNA methylation patterns, including methylation of inflammation- and iron- related genes. This highly collaborative proposal builds on the multi-disciplinary expertise of several research teams, joint preliminary data, and exceptional CHARTER Study resources. Importantly, it will leverage existing, NIH-funded projects within CHARTER by creating a rich, bi-genomic (nDNA and mtDNA) database linked to blood and cerebrospinal fluid (CSF) biomarker data and to meticulous neurocognitive assessments in 1000 subjects. We will use both state-of-the-art and novel computational approaches to characterize genomic regulation of HAND through three Specific Aims: 1) To determine effects of iron-related nDNA and mtDNA variants on neuroinflammatory biomarker levels in CSF; 2) To determine effects of nDNA and mtDNA variants on iron-related protein profiles and mononuclear-cell mtDNA copy number in CSF; and 3) to determine the proportion of HAND susceptibility that is attributable to nDNA (iron-related) and mtDNA genomic regulation of CSF intermediate phenotypes.