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）仍然是HIV感染的常见并发症，且对其了解甚少，影响死亡率，甚至发生在通过联合抗逆转录病毒治疗（cART）有效抑制病毒的个体中。HIV感染个体中HAND表达的广泛变异暗示其发病机制中的宿主基因组变异; 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。线粒体功能异常影响模型系统中的神经退行性过程，并且在人类神经认知障碍中很常见。中枢神经系统（CNS）中受调节的铁转运（尚未完全了解）对于正常线粒体功能（如氧化磷酸化（OXPHOS）和程序性细胞死亡的控制）至关重要;最近的研究还揭示了铁转运与炎症之间的密切联系。对影响铁代谢和线粒体OXPHOS的核DNA（nDNA）和不同线粒体DNA（mtDNA）基因组变体的协调研究可能会显着促进对复杂神经认知障碍（如HAND）的理解。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）中的作用的努力，作为与CNS HIV抗逆转录病毒治疗效果研究（CHARTER）研究组正在进行的合作的一部分。基于我们的发现和迄今为止的文献，我们假设影响铁转运和线粒体OXPHOS的nDNA和mtDNA变体独立地和共同地影响中间HAND相关表型，例如CSF中的炎症生物标志物水平、通过脑脊液（CSF）中的铁相关蛋白水平证明的穿过血脑屏障的铁转运、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。这个高度合作的提案建立在多个研究团队的多学科专业知识，联合初步数据和特殊的CHARTER研究资源的基础上。重要的是，它将利用CHARTER中现有的NIH资助的项目，创建一个丰富的双基因组（nDNA和mtDNA）数据库，该数据库与血液和脑脊液（CSF）生物标志物数据以及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的计算方法来表征HAND的基因组调控，通过三个特定的目的：1）确定铁相关的nDNA和mtDNA变体对CSF中神经炎性生物标志物水平的影响; 2）确定nDNA和mtDNA变体对CSF中铁相关蛋白质谱和单核细胞mtDNA拷贝数的影响;和3）确定归因于CSF中间表型的nDNA（铁相关）和mtDNA基因组调控的HAND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.