Host epigenetic and mitochondrial function in HIV-infected children

HIV感染儿童的宿主表观遗传和线粒体功能

• 批准号: 8703154
• 负责人: Louise Kuhn
• 金额: $ 71.48万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8703154
• 关键词: 2 year old; 9 year old; Acute; Adherence; Adult; Africa South of the Sahara; Aftercare; Age; Aging; Anti-Retroviral Agents; Automobile Driving; Biological Models; Blood specimen; Caring; Cellular Stress; Child; Chronic; Clinical; Clinical Data; Clinical Research; Clinical Trials; Comorbidity; DNA Methylation; Data; Databases; Development; Developmental Process; Disease; Disease Progression; Dyslipidemias; Enrollment; Ensure; Enzymes; Epidemiologic Studies; Epidemiology; Epigenetic Process; Etiology; Event; Fatty acid glycerol esters; Frequencies; Functional disorder; Future; Genes; Grant; HIV; HIV Infections; Health; Household; Immune; Infection; Inflammation; Intervention; Investigation; Laboratories; Life; Lipodystrophy; Long-Term Effects; Maintenance; Malignant Neoplasms; Measures; Metabolic; Methodology; Methods; Mitochondria; Mitochondrial DNA; Natural History; Neurologic; Outcome; Participant; Pathogenesis; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Population; Protocols documentation; Recruitment Activity; Regimen; Research; Resources; Role; Sampling; School-Age Population; Siblings; Site; South Africa; Specimen; Technology; Test Result; Testing; Time; Tissues; Toxic effect; age related; antiretroviral therapy; base; cohort; follow-up; improved; infancy; interest; mitochondrial dysfunction; novel; prospective; pyrosequencing; repository; senescence; treatment site

DESCRIPTION (provided by applicant): Perinatally HIV-infected children provide a unique model system to study the chronic effects of growing up with HIV. We propose to re-enroll 500 HIV-infected children age 5-9 years at two treatment sites in Johannesburg, South Africa. These children are prior participants in clinical studies who initiated therapy during the first two year of life and have detailed clinical information, HIV-related laboratory results and over 10,000 blood specimens stored in repositories. We will prospectively follow the re-enrolled children and collect standardized clinical data on co-morbidities, toxicities and complications, laboratory data on HIV-related parameters and blood samples and other specimens for special studies. We will also enroll a cross-sectional sample of 250 uninfected children (household/sibling controls) frequency-matched by age within 3-month intervals to the re- enrolled children at the time of recruitment. We will integrate the newly-collected, follow-up data and samples with the historical databases and repositories to provide a platform to investigate (1) host epigenetics and (2) mitochondrial function and their relations with HIV disease progression, drug regimens, and metabolic complications in HIV-infected children. First, using well-established array-based methods and pyrosequencing, we propose to identify the spectrum of gene-specific DNA methylation changes that accompany perinatally- acquired HIV infection and HIV treatment. Second, utilizing both stored and newly-collected specimens, we propose to test whether mitochondrial dysfunction (as measured by novel methods of enzyme function and cell stress) exacerbates chronic inflammation and immune senescence underlying HIV disease progression and the metabolic complications that may accompany long-term treatment. Our prospective cohort, building on an extensive and well-characterized perinatally-infected population, will provide a valuable resource to undertake these and future pathogenesis-oriented studies to inform development of complementary interventions to improve long-term outcomes of HIV-infected children in sub-Saharan Africa.

描述（由申请人提供）：围产期感染艾滋病毒的儿童提供了一个独特的模型系统来研究感染艾滋病毒长大的慢性影响。我们建议在南非约翰内斯堡的两个治疗点重新招募 500 名 5-9 岁的艾滋病毒感染儿童。这些儿童是临床研究的先期参与者，他们在生命的头两年内开始接受治疗，并拥有详细的临床信息、艾滋病毒相关实验室结果以及存储在存储库中的 10,000 多个血液样本。我们将前瞻性地跟踪重新入组的儿童，收集有关合并症、毒性和并发症、实验室数据的标准化临床数据 对艾滋病毒相关参数和血液样本及其他标本进行专门研究。我们还将招募 250 名未感染儿童（家庭/兄弟姐妹对照）的横断面样本，按年龄在 3 个月的间隔内与招募时重新登记的儿童进行频率匹配。我们将把新收集的后续数据和样本与历史数据库和存储库整合起来，提供一个平台来研究（1）宿主表观遗传学和（2）线粒体功能及其与艾滋病毒疾病进展、药物治疗和代谢的关系艾滋病毒感染儿童的并发症。首先，我们建议使用成熟的基于阵列的方法和焦磷酸测序来确定伴随围产期获得性 HIV 感染和 HIV 治疗的基因特异性 DNA 甲基化变化谱。其次，利用储存的和新收集的样本，我们建议测试线粒体功能障碍（通过酶功能和细胞应激的新方法测量）是否会加剧艾滋病毒疾病进展和可能伴随长期感染的代谢并发症的慢性炎症和免疫衰老。短期治疗。我们的前瞻性队列建立在广泛且特征明确的围产期感染人群的基础上，将为开展这些和未来的发病机制研究提供宝贵的资源，为制定补充干预措施提供信息，以改善亚裔艾滋病毒感染儿童的长期结果。 -撒哈拉非洲。