Genetic and Epigenetic Regulation of COMT, a Key Moderator of Cognitive Decline

COMT 的遗传和表观遗传调控，认知衰退的关键调节因素

• 批准号: 10178117
• 负责人: THERESA SWIFT-SCANLAN
• 金额: $ 41.54万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-10 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10178117
• 关键词: Alcohols; Alzheimer' s Disease; American; Amino Acid Substitution; Attention deficit hyperactivity disorder; Automobile Driving; Biological Markers; Brain; Brain region; Caregiver Burden; Catechol Estrogens; Catechol O-Methyltransferase; Catecholamines; Cell Line; Chemotherapy-Oncologic Procedure; Clinical; Complex; DNA; DNA Methylation; Data; Decitabine; Discipline of Nursing; Disease; Distal; Dopamine; Economic Burden; Enzymes; Epigenetic Process; Estradiol; Etiology; Executive Dysfunction; Expenditure; Exposure to; Foundations; Future; GTP-Binding Protein alpha Subunits, Gs; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Glean; Goals; Health; Healthcare; Hormones; Human; Human Cell Line; Impaired cognition; In Vitro; Individual Differences; Intervention; Knowledge; Measures; Mediator of activation protein; Medicaid; Membrane; Mental Depression; Messenger RNA; Metabolic; Methylation; Methyltransferase Gene; Modification; Nerve Degeneration; Neurobiology; Norepinephrine; Parkinson Disease; Peripheral; Population; Post-Traumatic Stress Disorders; Protein Isoforms; Protein O-Methyltransferase; Proteins; Public Health; Regulation; Research; Risk; Risk Factors; Risk Management; Schizophrenia; Specificity; Substance Use Disorder; Symptoms; Testing; Therapeutic; Therapeutic Intervention; Tissues; Transcript; Variant; base; behavioral pharmacology; cancer pain; cancer risk; carcinogenicity; cell type; chemotherapy; cognitive benefits; cognitive function; cost; differential expression; enzyme activity; epigenetic marker; epigenetic regulation; executive function; experience; genetic variant; healthy aging; improved; inhibitor/antagonist; mRNA Expression; metabolomics; normal aging; novel therapeutic intervention; overexpression; pain sensitivity; predictive marker; promoter; symptom management

PROJECT SUMMARY/ ABSTRACT Although cognitive decline (CD) and impairment are widespread and exact an enormous healthcare burden, therapeutic options are limited partly due to our incomplete understanding of the neurobiological bases of CD. Across conditions, including Alzheimer's, and Parkinson's Disease, worsening CD is commonly associated with high activity of the catechol-O-methyltransferase (COMT) enzyme. Such high activity can occur as a consequence of genetic variation in the COMT gene. The most studied COMT genetic polymorphism, rs4680, is an A→G change that yields a 4-fold difference in COMT enzyme activity. COMT breaks down catecholamines, and is the primary regulator of dopamine clearance in cortical brain regions; it also detoxifies carcinogenic catechol-estrogens. There are two COMT isoforms, which encode soluble (S-COMT) and membrane bound (MB-COMT) forms of the enzyme, respectively. Interventions that inhibit COMT can improve cognitive function, presumably by elevating cortical dopamine. However, while inhibiting MB-COMT, which dominates in the brain, shows cognitive benefit, no COMT inhibitors to date are isoform selective, and inhibition of S-COMT increases circulating carcinogenic catechol-estrogens, as well as peripheral catecholamines, increasing hormone-sensitive cancer risk, and pain sensitivity, respectively. While the evidence is strong that COMT genetic variation alters enzyme function, growing evidence also points to the influence of epigenetic COMT regulation, e.g., DNA methylation, in moderating COMT gene expression and bulk enzyme activity. Thus, the ability to selectively downregulate MB-COMT expression holds tremendous promise as a therapeutic intervention for CD across a broad array of conditions. Nevertheless, major mechanistic gaps persist: 1) There currently is no efficient way to distinguish and accurately measure MB- and S-COMT transcripts, and COMT protein isoforms haven't been measured in tandem with COMT mRNAs; 2) DNA methylation remains to be completely interrogated throughout regions thought to regulate MB- and S-COMT mRNA expression; and 3) the metabolites driving observed epigenetic modification of COMT, and their isoform specificity, are unknown. We therefore propose an in vitro study as a necessary first step in understanding the effects of metabolites and other epigenetic regulators on isoform-specific COMT expression in human cell lines. We expect to identify compounds regulating COMT, and their underlying epigenetic mechanisms, which will identify both biomarkers of CD risk and targets for new interventions for CD. Such future interventions may be particularly useful in combating executive function deficits, which is an aspect of CD common to a broad array of conditions, including normal aging, multiple neurodegenerative conditions, schizophrenia, ADHD, PTSD, depression, substance use disorders, and cancer chemotherapy treatment. As epigenetic marks can be reversed, a better understanding of isoform-specific regulation of COMT will be transformative in identifying new strategies for treating and delaying CD in these populations, substantially reducing their clinical and public health burden.

项目摘要/摘要 尽管认知能力下降（CD）和障碍是广泛的，并且是巨大的医疗保健伯恩（Burnen），但 治疗选择受到限制，部分原因是我们对CD神经生物学基础的不完全理解。 在包括阿尔茨海默氏症和帕金森氏病在内的疾病中，担心CD通常与 Catechol-O-甲基转移酶（COMT）酶的高活性。这样的高活动可能会作为 COMT基因遗传变异的结果。最研究的COMT遗传多态性RS4680是 A→G变化在COMT酶活性上产生4倍差异。 COMT分解儿茶酚胺， 是皮质大脑区域多巴胺清除率的主要调节剂；它也会解毒 儿茶酚 - 雌激素。有两个COMT同工型，它们编码固体（S-COMT）和膜结合 （MB-COMT）酶的形式。抑制COMT的干预措施可以改善认知功能， 大概是通过升高皮质多巴胺。但是，虽然抑制在大脑中占主导地位的MB-COMT，但 显示认知益处，迄今为止没有COMT抑制剂是同工型的选择性，S-COMT的抑制作用增加 循环致癌儿茶素雌激素以及周围儿茶酚胺，增加了马龙敏感的 癌症风险和疼痛敏感性。尽管有证据表明COMT遗传变异会改变 酶功能，越来越多的证据也表明表观遗传学调节的影响，例如DNA 甲基化，调节COMT基因表达和大量酶活性。那，有选择的能力 下调MB-COMT表达具有巨大的希望，作为CD的治疗干预措施 广泛的条件。但是，主要的机理差距仍然存在：1）当前没有有效的方法 尚未区分并准确测量MB和S-COMT转录本，而COMT蛋白质同工型尚未 与COMT mRNA同时测量； 2）DNA甲基化仍有待完全审问 被认为调节MB和S-COMT mRNA表达的区域； 3）观察到的代谢产物 COMT及其同工型特异性的表观遗传修饰尚不清楚。因此，我们提出了体外 研究是理解代谢物和其他表观遗传调节剂对的必要第一步 人细胞系中的同工型特异性COMT表达。我们希望确定调节COMT的化合物，并 它们的基本表观遗传机制将确定CD风险的生物标志物和新的目标 CD的干预措施。这种未来的干预措施可能在打击执行功能不足时特别有用， 这是广泛条件的CD的一个方面，包括正常衰老，多个 神经退行性疾病，精神分裂症，ADHD，PTSD，抑郁，药物使​​用障碍和癌症 化学疗法治疗。由于表观遗传标记可以逆转，因此可以更好地理解同工型特异性 COMT的调节将具有变革性的变革性，以确定在其中处理和延迟CD的新策略 人口大大减少了他们的临床和公共卫生伯恩。