Mitochondrial Heteroplasmy as an Endophenotype of HIV-Associated Neurocognitive Disorders

线粒体异质性作为 HIV 相关神经认知障碍的内表型

• 批准号: 9982450
• 负责人: ASHA R KALLIANPUR
• 金额: $ 20.46万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-23 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9982450
• 关键词: Age; Aging; Alleles; Animal Model; Automobile Driving; Base of the Brain; Biogenesis; Biological Markers; Cardiovascular Diseases; Catalogs; Cells; Cerebrospinal Fluid; Chronic; Cognition; Cognition Disorders; Cognitive; Collaborations; Complex; Cross-Sectional Studies; DNA; DNA Sequence; DNA copy number; DNA sequencing; Data; Degenerative Disorder; Detection; Development; Disease; Elderly; Energy Metabolism; Framingham Heart Study; Frequencies; Genes; Genome; Genomics; HIV; HIV Infections; HIV Seronegativity; HIV antiretroviral; HIV-associated neurocognitive disorder; Homeostasis; Impairment; Individual; Inflammation; Inherited; Iron; Lead; Link; Longevity; Measurement; Measures; Mediating; Metabolic Diseases; Methods; Mitochondria; Mitochondrial DNA; Monitor; Mutation; Neurocognitive; Neurocognitive Deficit; Neurodegenerative Disorders; Neurons; Neuropathogenesis; Nuclear; Organelles; Oxidative Stress; Participant; Pathogenicity; Performance; Peripheral Blood Mononuclear Cell; Persons; Phenotype; Play; Population; Public Health; Publishing; Quality of life; Regimen; Research; Risk; Role; Technology; Testing; Time; Tissues; Virus; Visit; age related; antiretroviral therapy; base; cognitive performance; cohort; comorbidity; deep sequencing; effective therapy; endophenotype; experience; follow-up; functional status; human disease; improved; insight; iron metabolism; longitudinal analysis; mitochondrial DNA mutation; mitochondrial dysfunction; neurocognitive disorder; neuroinflammation; neurosensory; next generation; next generation sequencing; non-invasive monitor; nonsynonymous mutation; novel; novel strategies; treatment strategy; virology

ABSTRACT HIV-Associated Neurocognitive Disorders (HAND) and other aging-related degenerative and metabolic disorders occur with excess frequency among people living with HIV infection (PLWH), despite antiretroviral therapy and virologic suppression. Abnormal function of energy generators within cells (mitochondria) plays an important role in these complex disorders, but the basis for these abnormalities is, for the most part, unknown. While inherited mitochondrial DNA (mtDNA) mutations have been studied in relation to complex human diseases, the impact of mtDNA mutations acquired over the lifespan of an individual is only just beginning to emerge, due to the power of next-generation DNA sequencing technologies that are essential for their detection. The presence of multiple mtDNA copies within each cell in an individual (and hence many coexisting types of mtDNA) defines mitochondrial heteroplasmy, and low-frequency pathogenic, as well as common heteroplasmic mutations increase with age, even in healthy individuals, potentially crossing tissue-specific thresholds for causing disease. Some studies suggest increased mtDNA mutations and/or expansion of pre-existing heteroplasmies during HIV infection and chronic treatment. Associations between heteroplasmy and cognitive disorders and other diseases have been made outside the HIV setting. This proposal will investigate the role of mitochondrial heteroplasmy in HAND, as well as its association with known correlates of aging and HAND. A better understanding of these relationships may lead to novel risk-monitoring and treatment strategies aimed at improving mitochondrial function and reducing the risk of HAND in PLWH. We propose to leverage a unique, longitudinal aging study among PLWH, and a similarly selected HIV(-) comparison population to implement the following Specific Aims: 1) Compare changes in mtDNA heteroplasmy over a 12-year period between PLWH on antiretroviral therapy and HIV-seronegative individuals; 2a) Determine relationships between mtDNA heteroplasmy and biomarkers of cerebrospinal-fluid inflammation, oxidative stress, and systemic iron status in PLWH on suppressive antiretroviral therapy; and 2b) Determine associations of mtDNA heteroplasmy with mtDNA copy number and measures of neurocognitive performance in cross-sectional and longitudinal analyses in PLWH. For this purpose, 100 PLWH and 25 age-matched HIV-seronegative individuals will undergo deep sequencing of mtDNA and measurement of mtDNA copy number at baseline and 10-12-yr follow-up visits. Heteroplasmy associations with measured iron status and existing age- and oxidative stress biomarkers will also be performed in PLWH. The team we have assembled for this purpose has expertise in state-of-the-art next-generation sequencing methods, mtDNA heteroplasmy studies in large cohorts, and in iron-mitochondrial genomics of neuroinflammation and HAND.

抽象的 与HIV相关的神经认知障碍（手）和其他与衰老有关的退行性和代谢 尽管抗逆转录病毒，但疾病感染患者（PLWH）的频率过多。 治疗和病毒学抑制。细胞内能量发生器的异常功能（线粒体）发挥 在这些复杂疾病中的重要作用，但是这些异常的基础在大多数情况下是未知的。 虽然已经研究了遗传性线粒体DNA（mtDNA）突变，但与复杂的人类疾病有关 在一个人的寿命中获得的mtDNA突变的影响才刚刚开始出现 对于下一代DNA测序技术的力量，这对于它们的检测至关重要。存在 每个单元中每个单元中的多个mtDNA副本（因此，许多共存的mtDNA类型）定义了 线粒体异质和低频致病性以及常见的杂质突变 随着年龄的增长，即使在健康的个体中，也可能越过组织特异性阈值引起疾病。 一些研究表明，艾滋病毒期间杂种杂质的mtDNA突变增加和/或膨胀 感染和慢性治疗。异质与认知障碍与其他疾病之间的关联 已经在艾滋病毒设置之外制作。该提议将研究线粒体异质在 手，及其与已知的衰老和手相关的关联。更好地理解这些 关系可能导致新颖的风险监测和治疗策略旨在改善线粒体 功能并降低PLWH中的手的风险。我们建议利用独特的纵向老化研究 在PLWH和类似选择的艾滋病毒（ - ）比较人群以实现以下特定目的： 1）比较抗逆转录病毒治疗的PLWH之间的12年中mtDNA异质性的变化 和艾滋病毒的个体； 2a）确定mtDNA异质和生物标志物之间的关系 抑制性的脑脊液 - 流体炎症，氧化应激和全身铁状态 抗逆转录病毒疗法；和2b）确定mtDNA异质性与mtDNA拷贝数和 PLWH中横截面和纵向分析中神经认知性能的度量。为此， 100个PLWH和25年龄匹配的HIV辅助个体将接受mtDNA的深度测序 在基线和10-12年的随访时测量mtDNA拷贝数。与 测量的铁状态以及现有的年龄和氧化应激生物标志物也将在PLWH中进行。这 为此，我们为此目的而组装的团队在最先进的下一代测序方法方面具有专业知识， mtDNA在大型同类群中的杂质研究以及神经炎症和神经炎症的铁质基因组学和 手。