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; 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相关的神经认知障碍（手）仍然普遍存在且了解艾滋病毒感染的并发症，影响死亡率，甚至在通过抗逆转录病毒疗法（CART）有效抑制病毒抑制的个体中也发生。 HIV感染个体中手表达的广泛差异暗示其发病机理中宿主的基因组变异。 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疾病中很常见。未完全理解的中枢神经系统（CNS）中的受调节铁转运对于正常的线粒体功能（例如氧化磷酸化（OXPHOS）（OXPHOS）和对程序性细胞死亡的控制）至关重要。最近的研究还揭示了铁运输与炎症之间的紧密联系。核DNA（NDNA）和影响铁代谢和线粒体Oxphos的不同线粒体DNA（mtDNA）基因组的变体的协调研究可能会显着提高人们对复杂神经认知障碍（如手）的理解。我们的研究团队领导了努力，以了解与CNS HIV HIV抗逆转录病毒治疗效应研究（CHARTER）研究小组的持续合作的一部分，包括外周神经病在内的与铁相关的NDNA基因和MTDNA在包括周围神经病在内的并发症中的作用。 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。这项高度协作的建议基于几个研究团队，联合初步数据和出色的宪章研究资源的多学科专业知识。重要的是，它将通过创建与血液和脑脊液（CSF）生物标志物数据相关的丰富，双基因组（NDNA和mtDNA）数据库来利用宪章中现有的，由NIH资助的项目，并在1000名受试者中与精心的神经认知评估相关联。我们将同时使用最新的和新颖的计算方法来表征手的基因组调节，通过三个特定目的：1）确定与CSF中与铁相关的NDNA和mtDNA变体对神经炎性生物标志物水平的影响； 2）确定NDNA和mtDNA变体对CSF中与铁相关蛋白谱和单核细胞mtDNA拷贝数的影响； 3）确定归因于NDNA（与铁相关）和MTDNA基因组调节CSF中间表型的手动敏感性的比例。