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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目概要/摘要尽管认知能力下降（CD）和损伤很普遍，并且造成了巨大的医疗负担，治疗选择受到限制，部分原因是我们对克罗恩病的神经生物学基础的了解不完全。在包括阿尔茨海默病和帕金森病在内的多种疾病中，CD 恶化通常与儿茶酚-O-甲基转移酶（COMT）的高活性可以作为一种酶发生。 COMT 基因遗传变异的结果研究最多的 COMT 遗传多态性是 rs4680。 A→G 的变化导致 COMT 酶活性相差 4 倍，COMT 分解儿茶酚胺，是大脑皮层区域多巴胺清除的主要调节剂，它还能解毒致癌物质；儿茶酚雌激素有两种 COMT 亚型，编码可溶性 (S-COMT) 和膜结合型。 (MB-COMT) 形式的酶，抑制 COMT 的干预措施可以改善认知功能，据称是通过提高皮质多巴胺，然而，在抑制大脑中占主导地位的 MB-COMT 的同时，显示出认知益处，迄今为止没有 COMT 抑制剂具有异构体选择性，并且 S-COMT 的抑制增加循环致癌儿茶酚雌激素以及外周儿茶酚胺，增加激素敏感性癌症风险和疼痛敏感性，虽然有强有力的证据表明 COMT 遗传变异会改变。酶功能，越来越多的证据也指出了表观遗传 COMT 调节的影响，例如 DNA 甲基化，调节 COMT 基因表达和大量酶活性，因此具有选择性的能力。下调 MB-COMT 表达作为 CD 的治疗干预具有巨大的前景然而，主要的机制差距仍然存在：1）目前没有有效的方法来实现这一目标。区分并准确测量 MB- 和 S-COMT 转录本，而 COMT 蛋白亚型尚未被 2）DNA甲基化仍有待彻底探究被认为调节 MB- 和 S-COMT mRNA 表达的区域；3) 观察到的驱动代谢物； COMT 的表观遗传修饰及其亚型特异性尚不清楚，因此我们提出了体外研究。研究是了解代谢物和其他表观遗传调节剂对细胞的影响的必要的第一步我们期望鉴定出调节 COMT 的化合物，以及它们潜在的表观遗传机制，将确定 CD 风险的生物标志物和新的目标此类未来的干预措施可能对对抗执行功能缺陷特别有用，这是 CD 的一个常见症状，常见于多种疾病，包括正常衰老、多种疾病神经退行性疾病、精神分裂症、多动症、创伤后应激障碍、抑郁症、药物滥用障碍和癌症由于表观遗传标记可以逆转，因此可以更好地了解异构体特异性。 COMT 的监管将在确定治疗和延缓 CD 的新策略方面具有变革性人群，大大减轻他们的临床和公共卫生负担。