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

神经炎症和手部的铁和线粒体基因组学：一项宪章研究

• 批准号: 8658731
• 负责人: TODD M HULGAN
• 金额: $ 52.17万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8658731
• 关键词: AIDS Dementia Complex; Affect; Aging; Apoptosis; Astrocytes; Biological Markers; Biological Models; Blood; Blood - brain barrier anatomy; Brain; Carrier Proteins; Cells; Central Nervous System Diseases; Cerebrospinal Fluid; Clinical; Clinical Trials Design; Cohort Studies; Collaborations; Complex; DNA; DNA Databases; DNA Methylation; DNA Sequence; DNA copy number; Data; Degenerative Disorder; Discipline; Disease; Disease Progression; Funding; Future; Genes; Genome; Genomic DNA; Genomics; Goals; HIV; HIV Infections; HIV-1; Health; Human; Impairment; Incidence; Individual; Inflammation; Integration Host Factors; Iron; Joints; Learning; Level of Evidence; Link; Literature; Measurement; Measures; Methylation; Minor; Mitochondria; Mitochondrial DNA; Modeling; Mononuclear; Nerve Degeneration; Neuraxis; Neurocognitive; Neurologic; Nuclear; Oligodendroglia; Outcome; Oxidative Phosphorylation; Pathogenesis; Pathway interactions; Patients; Pattern; Peripheral Nervous System Diseases; Persons; Phenotype; Population; Predisposition; Process; Proteins; Public Health; Regulation; Regulator Genes; Regulatory Pathway; Relative (related person); Research; Research Personnel; Research Subjects; Resources; Risk; Role; Severities; Short-Term Memory; Specimen; Stratification; Study Subject; Testing; United States National Institutes of Health; Variant; Viral; Work; antiretroviral therapy; base; cohort; executive function; experience; gene interaction; genome wide association study; improved; iron metabolism; mortality; neuroinflammation; novel; prevent; protein profiling; research study

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.

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，但人们对 HIV 感染并发症知之甚少，它会影响死亡率，甚至在通过联合抗逆转录病毒疗法 (cART) 有效抑制病毒的个体中也会出现这种情况。 HIV 感染者中 HAND 表达的广泛变异表明其发病机制中存在宿主基因组变异； HIV 疾病进展、神经炎症和 cART 线粒体效应的相对影响尚不清楚。线粒体功能异常会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) 中的铁转运调节机制目前尚不完全清楚，但它对于氧化磷酸化 (OXPHOS) 等正常线粒体功能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) 和独特线粒体 DNA (mtDNA) 基因组变异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。作为与 CNS HIV 抗逆转录病毒治疗效果研究 (CHARTER) 研究小组持续合作的一部分，我们的研究团队致力于了解铁相关 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。根据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 变异独立并共同影响中间 HAND 相关表型，例如脑脊液中的炎症生物标志物水平、铁跨血脑屏障的转运脑脊液 (CSF) 中铁相关蛋白的水平、线粒体 DNA 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）即可证明。这项高度协作的提案建立在多个研究团队的多学科专业知识、联合初步数据和卓越的 CHARTER 研究资源的基础上。重要的是，它将利用 CHARTER 内现有的 NIH 资助项目，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。我们将使用最先进和新颖的计算方法，通过三个具体目标来表征 HAND 的基因组调控：1）确定铁相关 nDNA 和 mtDNA 变体对 CSF 中神经炎症生物标志物水平的影响； 2) 确定 nDNA 和 mtDNA 变异对 CSF 中铁相关蛋白谱和单核细胞 mtDNA 拷贝数的影响； 3) 确定可归因于 CSF 中间表型的 nDNA（铁相关）和 mtDNA 基因组调节的 HAND 易感性比例。