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:9762219
- 负责人:
- 金额:$ 41.36万
- 依托单位:
- 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:
- 关键词:AlcoholsAlzheimer&aposs DiseaseAmericanAmino Acid SubstitutionAttention deficit hyperactivity disorderAutomobile DrivingBiological MarkersBrainBrain regionCaregiver BurdenCatechol EstrogensCatechol O-MethyltransferaseCatecholaminesCell LineChemotherapy-Oncologic ProcedureClinicalComplexDNADNA MethylationDataDecitabineDiscipline of NursingDiseaseDistalDopamineEconomic BurdenEnzymesEpigenetic ProcessEstradiolEtiologyExecutive DysfunctionExpenditureExposure toFoundationsFutureGTP-Binding Protein alpha Subunits, GsGene ExpressionGenesGeneticGenetic PolymorphismGenetic VariationGenotypeGleanGoalsHealthHealthcareHormonesHumanHuman Cell LineImpaired cognitionIn VitroIndividual DifferencesInterventionKnowledgeMeasuresMediator of activation proteinMedicaidMembraneMental DepressionMessenger RNAMetabolicMethylationMethyltransferase GeneModificationNerve DegenerationNeurobiologyNorepinephrineParkinson DiseasePeripheralPopulationPost-Traumatic Stress DisordersProtein IsoformsProtein O-MethyltransferaseProteinsPublic HealthRegulationResearchRiskRisk FactorsRisk ManagementSchizophreniaSpecificitySubstance Use DisorderSymptomsTestingTherapeuticTherapeutic InterventionTissuesTranscriptVariantbasebehavioral pharmacologycancer paincancer riskcarcinogenicitycell typechemotherapycognitive benefitscognitive functioncombatcostdifferential expressionenzyme activityepigenetic markerepigenetic regulationexecutive functionexperiencegenetic varianthealthy agingimprovedinhibitor/antagonistmRNA Expressionmetabolomicsnormal agingnovel therapeutic interventionoverexpressionpain sensitivitypredictive markerpromotersymptom 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.
项目总结/摘要
虽然认知能力下降(CD)和损害是普遍的,确切的一个巨大的医疗保健负担,
部分由于我们对CD的神经生物学基础的不完全理解,治疗选择是有限的。
在包括阿尔茨海默病和帕金森病在内的各种疾病中,CD恶化通常与
儿茶酚-O-甲基转移酶(COMT)的高活性。这种高活性可以作为一种
COMT基因遗传变异的结果。研究最多的COMT遗传多态性rs 4680是
A→G的变化导致COMT酶活性的4倍差异。COMT分解儿茶酚胺,
是大脑皮质区多巴胺清除的主要调节剂;它也能解毒致癌物质
儿茶酚雌激素COMT有两种亚型,分别编码可溶性(S-COMT)和膜结合型(S-COMT
(MB-COMT)形式的酶。抑制COMT的干预可以改善认知功能,
可能是通过提高皮质多巴胺然而,在抑制在大脑中占主导地位的MB-COMT的同时,
显示认知益处,迄今为止没有COMT抑制剂是亚型选择性的,并且S-COMT的抑制增加
循环致癌的儿茶酚-雌激素,以及外周的儿茶酚胺,增加对激素敏感的
癌症风险和疼痛敏感性。虽然有强有力的证据表明COMT基因变异改变了
酶的功能,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基因表达和整体酶活性。因此,选择性地
下调MB-COMT表达作为CD的治疗干预具有巨大的前景,
各种各样的条件。然而,主要的机械差距仍然存在:1)目前没有有效的方法来
区分和准确测量MB-和S-COMT转录本,COMT蛋白亚型还没有被发现。
与COMT mRNAs串联测量; 2)DNA甲基化仍然需要在整个过程中完全询问
被认为调节MB-和S-COMT mRNA表达的区域;和3)观察到的代谢物驱动
COMT的表观遗传修饰及其同种型特异性是未知的。因此,我们建议在体外
研究作为了解代谢物和其他表观遗传调节剂对
人细胞系中同种型特异性COMT表达。我们希望能鉴定出调节COMT的化合物,
他们的潜在表观遗传机制,这将确定CD风险的生物标志物和新的靶点。
CD的介入。这种未来的干预措施可能在对抗执行功能缺陷方面特别有用,
这是CD的一个方面,常见于一系列广泛的条件,包括正常老化,多重
神经退行性疾病、精神分裂症、ADHD、PTSD、抑郁症、物质使用障碍和癌症
化疗由于表观遗传标记可以逆转,因此更好地了解亚型特异性
COMT的调节将在确定治疗和延迟CD的新策略方面具有变革性,
这大大减轻了他们的临床和公共卫生负担。
项目成果
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{{ truncateString('THERESA SWIFT-SCANLAN', 18)}}的其他基金
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 - 财政年份:2018
- 资助金额:
$ 41.36万 - 项目类别:
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:
10404592 - 财政年份:2018
- 资助金额:
$ 41.36万 - 项目类别: