Epigenetic and Psychosocial Drivers of NeuroHIV in HIV+ South African Adolescents

南非艾滋病毒青少年中 NeuroHIV 的表观遗传和心理社会驱动因素

• 批准号: 9275541
• 负责人: Jacqueline Hoare
• 金额: $ 23.64万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9275541
• 关键词: Acceleration; Adolescent; Adult; Age; Aging; Anti-Retroviral Agents; Automobile Driving; Biological; Biological Aging; Biological Markers; Biometry; Biostatistical Methods; Brain; California; Characteristics; Child; Childhood; Cognitive; Cohort Studies; Collaborations; Comorbidity; Complex; Cross-Sectional Studies; DNA; DNA Methylation; Data; Development; Diagnosis; Diffuse; Disease; Economics; Elements; Environment; Environmental Risk Factor; Epigenetic Process; Family; Functional Magnetic Resonance Imaging; Functional disorder; Funding; Genes; Genomics; Goals; HIV; HIV Infections; HIV-1; HIV-infected adolescents; Home environment; Image; Individual; Infection; Intervention; Investigation; Investments; Longevity; Los Angeles; Magnetic Resonance Imaging; Medical; Mental disorders; Methylation; Nervous System Physiology; Neurocognitive; Neurocognitive Deficit; Neurodegenerative Disorders; Neuropathogenesis; Neuropsychological Tests; Ontology; Pathogenesis; Pathway Analysis; Perinatal; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Postdoctoral Fellow; Process; Psychological Stress; Psychosocial Factor; Public Health; Recruitment Activity; Research; Research Personnel; Resources; Risk; Role; Sampling; South Africa; South African; Statistical Data Interpretation; Stress; Technology; Training; Translations; Universities; Youth; arm; cohort; cost; cost effectiveness; developmental disease; genome wide methylation; genome-wide; human subject; improved; indexing; longitudinal design; neurobehavioral; neurodevelopment; neuroimaging; neurophysiology; potential biomarker; psychosocial; public health relevance; treatment strategy; virology

 DESCRIPTION (provided by applicant): DNA methylation (DNAm), an epigenetic process, is critical for neurodevelopment and for neurologic functioning throughout the lifespan. Aberrations in DNAm result in developmental, neurodegenerative, and psychiatric disorders. We have discovered that HIV+ adults have altered DNAm in both brain and peripheral blood mononuclear cells, resulting in accelerated biological aging. Perinatally HIV-infected (PHIV+) children are at increased risk of neurodevelopmental delay and lasting neurocognitive dysfunction. In this study, we examine the role of DNAm in the neurocognitive development of PHIV+ adolescents, while also considering important psychosocial, medical, virologic, and other factors. The immediate goal of this study is to delineate the complex relationship between these various factors in the pathogenesis of neurocognitive deficits in PHIV+ adolescents. The intermediate goal is to utilize the information gained to develop intervention strategies aimed at improving the lives of PHIV+ children as they progress into adulthood. The long term aim of this study is to develop a biomarker of currently concealed neuropathological processes that result from HIV, so that appropriate interventions can be provided to at-risk youths. This study will consider a host of environmental factors known to impact neurodevelopment, including stress, antiretroviral (ARV) medication use, economic adversity, medical comorbidities, and home/family environment. It will leverage the extant resource of the Cape Town Adolescent Antiretroviral Cohort (CTAAC), thereby maximizing efficiency and cost effectiveness, while minimizing human subjects' burden. The combination of cross sectional and longitudinal aims will allow fast translation of the findings and true characterization of neurodevelopmental and cognitive divergences resulting from epigenetic dysregulation due to HIV. In addition, the genome-wide methylation data generated can be used to enhance other research arms of the CTAAC, maximizing the potential return of investment. We also include a capacity building element by funding a postdoctoral fellow from UCT to be trained in biostatistics by UCLA researchers. This study is possible through the collaboration of two teams: The University of Cape Town team, which is currently carrying out the CTAAC neuro sub-study involving 200 HIV+ and 50 HIV- adolescents with diffusor tensor imaging, comprehensive neuropsychological testing, and assessment of childhood psychosocial factors, will provide all data and biological samples, as well as expertise in neuroimaging and pediatric neuroHIV. The University of California - Los Angeles team, which has extensive expertise in epigenetic biostatistical methods and genomic investigations of neuroHIV will process DNA samples and conduct the statistical analyses.

 描述（由申请人提供）：DNA 甲基化 (DNAm) 是一种表观遗传过程，对于神经发育和整个生命周期的神经功能至关重要。 DNAm 畸变会导致发育、神经退行性疾病和精神疾病。我们发现，HIV阳性成年人的大脑和外周血单核细胞中的DNAm都发生了改变，导致生物衰老加速。围产期感染艾滋病毒（PHIV+）的儿童神经发育迟缓和持久神经认知功能障碍的风险增加。在这项研究中，我们研究了 DNAm 在 PHIV+ 青少年神经认知发展中的作用，同时也考虑了重要的心理社会、医学、病毒学和其他因素。本研究的直接目标是描绘 PHIV+ 青少年神经认知缺陷发病机制中这些不同因素之间的复杂关系。中期目标是利用获得的信息来制定干预策略，旨在改善 PHIV+ 儿童成年后的生活。这项研究的长期目标是开发一种目前隐藏的由艾滋病毒引起的神经病理过程的生物标志物，以便为高危青少年提供适当的干预措施。 这项研究将考虑许多已知影响神经发育的环境因素，包括压力、抗逆转录病毒 (ARV) 药物的使用、经济逆境、医疗合并症和家庭环境。它将利用开普敦青少年抗逆转录病毒队列（CTAAC）的现有资源，从而最大限度地提高效率和成本效益，同时最大限度地减少人类受试者的负担。横向和纵向目标的结合将有助于快速转化研究结果，并真实描述因艾滋病毒导致的表观遗传失调而导致的神经发育和认知差异。此外，生成的全基因组甲基化数据可用于增强 CTAAC 的其他研究部门，从而最大限度地提高潜在投资回报。我们还通过资助一名来自加州大学洛杉矶分校的博士后研究员接受加州大学洛杉矶分校研究人员的生物统计学培训，纳入了能力建设的内容。 这项研究是通过两个团队的合作得以实现的：开普敦大学团队目前正在进行 CTAAC 神经子研究，涉及 200 名 HIV+ 和 50 名 HIV-青少年，通过扩散张量成像、全面的神经心理学测试和儿童心理社会因素评估，将提供所有数据和生物样本，以及神经影像学和儿科神经 HIV 方面的专业知识。加州大学洛杉矶分校的团队在表观遗传生物统计方法和神经艾滋病毒基因组研究方面拥有丰富的专业知识，他们将处理 DNA 样本并进行统计分析。