Genetic Predictors of Cognition in HIV+ Women

描述（由申请人提供）：本申请提出了一个博士前培训计划，旨在确定人类免疫缺陷病毒（HIV）的认知表现和脑功能障碍的遗传预测因子。培训计划包括三个主要领域的指导、教学和体验性研究培训：1)艾滋病毒，2)功能性磁共振成像（fMRI）和3)心理遗传学。候选人的目标是建立在以前的训练在功能磁共振成像和遗传学，并进行一个论文项目，结合两种方法在一个新的方向。该项目将是实现申请人独立研究与遗传标记相关的认知和心理健康的职业目标的重要一步。在这个更广泛的目标中，拟议的研究培训计划的总体目标是表征儿茶酚- o -甲基转移酶（COMT）基因Val158Met的常见多态性对艾滋病毒感染的中年妇女认知和脑功能的影响。在这种特殊疾病中研究这种特殊基因型的动机来自于在健康成人中受到COMT影响的特定认知和神经机制的大量重叠，而在艾滋病毒感染者中则受到损害。我们的假设是，这种多态性加剧了这种疾病特征的认知脆弱性。数据表明，Val158Met多态性损害前额叶介导的认知和生理反应。Val等位基因与工作记忆任务中前额叶皮层的异常激活和处理效率下降有关。本项目旨在研究Val158Met多态性对中年HIV女性执行功能和前额皮质功能障碍的影响。数据将包括来自妇女跨机构艾滋病毒研究（WIHS）芝加哥站点的参与者。行为数据将包括在N-back上的表现，并将在大约240名妇女的日常WIHS研究访问中收集。我们预测与Val/Met和Met/Met基因型相比，Val/Val基因型的认知表现更差，并且与HIV对照组相比，Val/Val基因型对HIV阳性女性的负面影响更为明显。为了研究这种遗传易感性的神经基质，18名HIV阳性妇女将在进行N-back测试时接受功能磁共振成像评估。据预测，与没有这种等位基因的女性相比，Val等位基因携带者在N-back期间的前额皮质活动会增加。这项研究将首次评估COMT Val 158Met多态性与HIV人群认知之间的关系。

DESCRIPTION (provided by applicant): This application proposes a predoctoral training program aimed at identifying genetic predictors of cognitive performance and brain dysfunction in Human Immunodeficiency Virus (HIV). The training program involves mentored, didactic, and experiential research training in three primary areas: 1) HIV, 2) functional magnetic resonance imaging (fMRI) and 3) psychogenetics. The candidate aims to build on previous training in fMRI and genetics and to conduct a dissertation project that unites the two methods in a novel direction. The project would be an important step in achieving the applicant's career goal to independently research cognition and mental health in relation to genetic markers. Within this broader goal, the general aim of the proposed research training program is to characterize the effect of a common polymorphism of the catechol- O-methyl transferase (COMT) gene, Val158Met, on cognition and brain function in midlife women with HIV. The motivation for examining this particular genotype in this particular disease comes from the large overlap in the specific cognitive and neural mechanisms shown to be affected by COMT in healthy adults and to be impaired in individuals with HIV. The hypothesis is that this polymorphism compounds the cognitive vulnerabilities that characterize this disease. Data suggests that the Val158Met polymorphism impairs prefrontal-mediated cognition and physiological response. The Val allele has been associated with abnormal activation and decreased processing efficiency of the prefrontal cortex during working memory tasks. The proposed project aims to examine the effect of the Val158Met polymorphism on executive function and prefrontal cortex dysfunction in midlife women with HIV. Data will be included from participants of the Chicago site of the Women's Interagency HIV Study (WIHS). Behavioral data will include performance on the N-back and will be collected in approximately 240 women during their routine WIHS study visits. We predict worse cognitive performance with the Val/Val genotype compared with Val/Met and Met/Met genotypes, and that the negative effect of Val/Val genotype would be more pronounced in HIV+ women compared to HIV- controls. To investigate the neural substrates of this genetic vulnerability, 18 HIV+ women will undergo fMRI assessments during performance of an N-back test. It is predicted that Val allele carriers will show increased prefrontal cortex activity during the N-back compared to women without the allele. This study will be the first to evaluate relationships between the COMT Val 158Met polymorphism and cognition in an HIV population. PUBLIC HEALTH RELEVANCE: The findings will provide insight into genetic predictors of cognitive function in HIV+ women and will help identify a risk factor that may compound executive function deficits in the disease.