COMT Genotype and Executive Function in HIV Infection and Methamphetamine Use

HIV 感染和甲基苯丙胺使用中的 COMT 基因型和执行功能

• 批准号: 7752706
• 负责人: Ian Paul Everall
• 金额: $ 23.18万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7752706
• 关键词: 3-nitrotyrosine; Acids; Affect; Affinity; Age-Years; Alleles; Amino Acids; Attention; Binding; Blood; Brain; Brain region; Catechols; Cells; Codon Nucleotides; Corpus striatum structure; Data; Deposition; Deterioration; Development; Disease; Dopamine; Exons; Exposure to; Frequencies; Functional disorder; Funding; Future; Genes; Genetic; Genetic Polymorphism; Genotype; Goals; HIV; HIV Infections; HIV Seropositivity; High Pressure Liquid Chromatography; Homeostasis; Homovanillic Acid; Human; Impaired cognition; Impairment; In Vitro; Individual; Inflammation; Inherited; Interneurons; Investigation; Left; Life; Lipid Peroxidation; Measures; Mediating; Membrane; Methamphetamine; Methionine; Modeling; Molecular; National NeuroAids Tissue Consortium; Nerve Degeneration; Neurocognitive; Neurologic; Neurons; Oxidative Stress; Performance; Population; Positioning Attribute; Prefrontal Cortex; Process; Production; Proteins; Relative (related person); Research Project Grants; Role; Sampling; Short-Term Memory; Sorting - Cell Movement; Substantia nigra structure; Testing; Transferase; Transferase Gene; United States; United States National Institutes of Health; Valine; Variant; Ventral Tegmental Area; Wisconsin; brain tissue; calbindin; cognitive change; dopamine transporter; executive function; frontal cognitive dysfunction; frontal lobe; human fetus tissue; interest; male; meetings; methamphetamine exposure; methionylmethionine; neuron loss; neuroprotection; neuropsychological; oxidative DNA damage; prevent; programs; protective effect; public health relevance; synuclein; tissue culture; valylvaline

DESCRIPTION (provided by applicant): We propose to investigate the relationship between the inherited genotype of catechol-o-methyl transferase (COMT) and the protection against the development of HIV related impaired executive function, which is lost when methamphetamine (METH) is used by the affected individuals. We intend to focus on a common functional polymorphism, a Valine (Val) to Methionine (Met) substitution in exon 4 of the gene that alters the amino acid codon at position 108 (Val108Met) in the soluble-COMT (S-COMT) which is found in blood or position 158 (Val158Met) in the membrane-bound COMT (MB-COMT) located in the brain. This polymorphism results in a significant change in the enzymatic activity to degrade dopamine when the Val allele is not present. We have performed genotyping for the Val/Met alleles of the COMT gene in 270 subjects that include healthy controls; HIV infected/METH negative; METH positive/HIV uninfected; and HIV infected/METH positive individuals. We noted significantly lower levels of impairment in the healthy controls carrying a met allele and this allele continued to confer better executive functioning even in the HIV infected subjects. However, impairment of executive functioning was higher in the METH dependent and HIV infected/METH dependent groups regardless of COMT genotype with the protective effects of the met allele having been lost. The second finding is that in HIV infected individuals over 55 years that is a significant increase in the frequency of 1- synuclein deposition compared to controls. Our overarching hypothesis is that individuals with COMT-met allele conferred protection against HIV mediated frontal cognitive dysfunction, which is lost in the context of METH. We intend to assess the relationship between the inherited COMT genotype and documented meth use and executive function in life with neuropathological markers of neurodegeneration and inflammation in human brain tissue and in vitro human brain tissue cultures. Specifically we will assess the accumulation oxidative proteins, nitrotyrosine, lipid peroxidation, oxidative DNA damage and 1-synuclein deposition as these are associated with meth use and we have recently demonstrated a significant increase in 1-synuclein deposition in HIV infected individuals. We will further assess the molecular effects of methamphetamine to elucidate the process by which methamphetamine abrogates the protective effect of met/met COMT with the presumption that it may be related to oxidative stress. Such an understanding will in a future application facilitate the development of targeted therapies to prevent the methamphetamine related molecular dysfunction. PUBLIC HEALTH RELEVANCE: Methamphetamine users are the fastest growing population in the United States to acquire HIV infection. Furthermore, HIV infected methamphetamine users suffer the most severe cognitive impairment. In this investigation we are proposing to investigate the relationship between the inherited variant of the catechol-o-methyl-transferase (COMT) gene and HIV associated neurocognitive disorder (HAND) in methamphetamine users.

描述(由申请人提供)：我们建议调查儿茶酚-o-甲基转移酶(COMT)的遗传基因型与防止HIV相关执行功能受损的保护作用之间的关系，当受影响的个人使用甲基苯丙胺(METH)时，执行功能受损会丢失。我们打算集中在一个常见的功能多态，即基因外显子4的Valine(Val)到Met(Met)的替换，该基因改变了血液中发现的可溶性COMT(S-COMT)第108位(Val108 Met)的氨基酸密码子或位于大脑中的膜结合CoMT(MB-CoMT)第158位(Val158 Met)。当不存在Val等位基因时，这种多态会导致降解多巴胺的酶活性发生显著变化。我们对270例受试者进行了COMT基因Val/Met等位基因分型，其中包括健康对照组、HIV感染/冰毒阴性者、冰毒阳性/未感染者和HIV感染/冰毒阳性者。我们注意到，携带MET等位基因的健康对照组的损害水平明显较低，即使在HIV感染的受试者中，该等位基因也继续赋予更好的执行功能。然而，无论COMT基因型如何，冰毒依赖组和HIV感染/冰毒依赖组的执行功能受损程度都更高，MET等位基因的保护作用已经丧失。第二个发现是，在55岁以上的艾滋病毒感染者中，与对照组相比，1-突触核蛋白沉积的频率显着增加。我们的主要假设是，携带COMT-MET等位基因的人对HIV介导的额叶认知功能障碍具有保护作用，而这种功能在冰毒的背景下会丢失。我们打算通过人脑组织和体外人脑组织培养中神经变性和炎症的神经病理标记物，评估遗传的COMT基因与有记录的冰毒使用和生活中执行功能之间的关系。具体地说，我们将评估氧化蛋白、硝基酪氨酸、脂质过氧化、氧化DNA损伤和1-突触核蛋白沉积的积累，因为这些都与冰毒使用有关，而且我们最近已经证明，在HIV感染者中1-突触核蛋白沉积显著增加。我们将进一步评估甲基苯丙胺的分子效应，以阐明甲基苯丙胺取消MET/MET COMT的保护作用的过程，推测它可能与氧化应激有关。这样的理解将在未来的应用中促进靶向治疗的发展，以防止甲基苯丙胺相关的分子功能障碍。公共卫生相关性：冰毒使用者是美国感染艾滋病毒的增长最快的人口。此外，感染艾滋病毒的甲基苯丙胺使用者的认知障碍最严重。在这项研究中，我们建议研究儿茶酚氧位甲基转移酶(COMT)基因的遗传变异与甲基苯丙胺使用者中HIV相关神经认知障碍(HAND)的关系。