Genetic Predictors of Cognition in HIV+ Women

描述(由申请者提供)：该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)认知表现和脑功能障碍的遗传预测因素。该培训计划包括三个主要领域的指导性、教学性和体验式研究培训：1)艾滋病毒，2)功能磁共振成像(FMRI)和3)心理遗传学。候选人的目标是在之前的功能磁共振成像和遗传学培训的基础上，进行一个论文项目，将这两种方法统一在一个新的方向上。该项目将是实现申请人独立研究与遗传标记有关的认知和心理健康的职业目标的重要一步。在这一更广泛的目标范围内，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)基因的常见多态Val158Met对感染艾滋病毒的中年妇女的认知和脑功能的影响。在这种特殊疾病中检查这种特殊基因的动机来自于特定认知和神经机制的很大重叠，这些机制在健康成年人中受到COMT的影响，在艾滋病毒携带者中受到损害。假说是，这种多态加剧了这种疾病的认知脆弱性。数据表明，Val158Met基因多态损害了前额叶调节的认知和生理反应。在工作记忆任务中，Val等位基因与前额叶皮质的异常激活和处理效率降低有关。这项拟议的项目旨在检测Val158Met基因多态对携带艾滋病毒的中年女性执行功能和前额叶皮质功能障碍的影响。数据将包括芝加哥妇女机构间艾滋病毒研究(WIHS)网站的参与者。行为数据将包括在N-Back上的表现，并将在约240名妇女的常规WIHS研究访问期间收集。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Val/Val基因型的负面影响在HIV+女性中比HIV对照组更明显。为了研究这种遗传脆弱性的神经基础，18名HIV+女性将在N-Back测试期间接受功能磁共振评估。据预测，Val等位基因携带者在N-back过程中，与没有该等位基因的女性相比，前额叶皮质活动会增加。这项研究将首次评估COMT Val 158Met多态与HIV人群认知之间的关系。 公共卫生相关性：这些发现将为HIV+女性认知功能的遗传预测因素提供洞察力，并将有助于识别可能加剧该疾病执行功能缺陷的风险因素。

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.