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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

基本信息

批准号：
8190607
负责人：
Ian Paul Everall
金额：
$ 14.7万
依托单位：
UNIVERSITY OF MELBOURNE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8190607
关键词：
COMT Genotype Executive Function HIV

项目摘要

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）：我们建议研究儿茶酚-O-甲基转移酶（COMT）的遗传基因型与防止HIV相关执行功能受损发展之间的关系，当受影响的个体使用甲基苯丙胺（METH）时，执行功能受损会丧失。我们打算把重点放在一个共同的功能多态性，缬氨酸（瓦尔）到蛋氨酸（Met）取代在外显子4的基因，改变氨基酸密码子在位置108（Val 108 Met）的可溶性COMT（S-COMT），这是在血液中发现或位置158（Val 158 Met）的膜结合COMT（MB-COMT）位于大脑。当不存在瓦尔等位基因时，这种多态性导致降解多巴胺的酶活性的显著变化。我们对270名受试者的COMT基因的瓦尔/Met等位基因进行了基因分型，这些受试者包括健康对照、HIV感染/METH阴性、METH阳性/HIV未感染和HIV感染/METH阳性个体。我们注意到携带met等位基因的健康对照组的损伤水平显著较低，即使在HIV感染者中，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，METH依赖组和HIV感染/METH依赖组的执行功能受损程度均较高，其中met等位基因的保护作用已丧失。第二个发现是，在55岁以上的HIV感染者中，与对照组相比，1-突触核蛋白沉积的频率显著增加。我们的总体假设是，具有COMT-met等位基因的个体赋予了对HIV介导的额叶认知功能障碍的保护，这在METH的背景下是丢失的。我们打算用人脑组织和体外人脑组织培养物中神经变性和炎症的神经病理学标志物评估遗传COMT基因型与记录的冰毒使用和生活中的执行功能之间的关系。具体来说，我们将评估氧化蛋白质，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，因为这些都与冰毒的使用，我们最近已经证明了1-突触核蛋白沉积在HIV感染者显着增加。我们将进一步评估甲基苯丙胺的分子效应，以阐明甲基苯丙胺消除met/met COMT保护作用的过程，并推测其可能与氧化应激有关。这种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：甲基苯丙胺使用者是美国感染艾滋病毒增长最快的人群。此外，受艾滋病毒感染的甲基苯丙胺使用者遭受最严重的认知障碍。在这项调查中，我们建议调查儿茶酚-O-甲基转移酶（COMT）基因的遗传变异和甲基苯丙胺用户中的HIV相关神经认知障碍（HAND）之间的关系。