Age-Related Histone Modification Effect on Antipsychotic Action
年龄相关的组蛋白修饰对抗精神病作用的影响
基本信息
- 批准号:9281089
- 负责人:
- 金额:$ 38.63万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-05-26 至 2021-02-28
- 项目状态:已结题
- 来源:
- 关键词:AcetylationAdverse drug effectAdverse effectsAffectAgeAgingAlzheimer&aposs disease modelAnimal ModelAntipsychotic AgentsAnxietyBehaviorBehavioral ModelBehavioral SymptomsBrain regionChronicCognitiveComplexCorpus striatum structureDRD2 geneDataDementiaDevelopmentDopamineDoseDrug KineticsDrug TargetingDrug effect disorderElderlyEpigenetic ProcessFOS geneGene TransferGenesGeriatricsHTR2A geneHaloperidolHistone DeacetylaseHistone Deacetylase InhibitorHistonesIncidenceInterventionMS-275MeasuresMediatingMemoryMental disordersMethylationMotorMusNeurologicPatientsPharmaceutical PreparationsPharmacodynamicsPharmacologyPharmacotherapyPlayPopulationPsychiatric therapeutic procedurePsychopathologyReceptor GeneRegulationSerotoninSeveritiesSymptomsTestingTg2576TherapeuticValproic AcidViralVulnerable PopulationsWorkage relatedagedaging populationalternative treatmentbasebehavioral outcomeexperiencehistone modificationimprovedinterestmotor symptommouse modelneuropsychiatric disorderneuropsychiatrynovelnovel strategiesolder patientpromoterpsychological symptompublic health relevancereceptorreceptor bindingreceptor expressionreceptor functionresponserisk benefit ratiotreatment strategy
项目摘要
DESCRIPTION (provided by applicant): a common class of medication prescribed to the elderly for the treatment of psychiatric disorders and behavioral and psychological symptoms of dementia (BPSD). However, in aged patients, the incidence and severity of the side effects such as experiencing extrapyramidal motor symptoms induced by APDs is increased. Although aged-induced changes in pharmacokinetics may contribute to the increased sensitivity to the side effects of APDs in the elderly, age-related pharmacodynamic changes at the target receptor level likely play a key role in the increased sensitivity to the side effects of APDs. However, the
mechanisms underlying these age-related declines in receptor function are not well understood. Recently, we identified that histone modifications alter the therapeutic actions of a typical APD, haloperidol, in aged mice. In addition, our preliminary data in this application demonstrates that increases in the severity of extrapyramidal symptom-like side effects (motor side effects) in aged mice can be related to histone hypoacetylation of the dopamine 2 receptor (D2R) gene (Drd2) promoter that in turn decreases the expression of striatal D2Rs. Co- treatment with histone deacetylase inhibitors (HDACis) valproic acid (VPA) or entinostat (MS-275) restored the expression of striatal D2Rs and reduced age-related increases in the motor side effects of haloperidol. Our findings and preliminary results suggest that age-related histone modifications at the gene promoters of target receptors could affect APD action. In this proposal, we seek to confirm the novel epigenetic mechanisms underlying the regulation of APD action during aging and determine whether HDACis could be a candidate to improve APD treatment in the elderly. Our central hypothesis is that age-related increases in the motor side effects of APDs are due to histone hypoacetylation on their targeted receptor genes and that these epigenetic changes and their functional consequences can be reversed by co-treatment with HDACis. To test our hypotheses, first, we will verify that age-related histone modifications are one of the mechanisms underlying increased sensitivity to side effects induced by APDs. Then, we will identify the HDAC subtype(s) that contribute to histone modification and increase in the severity of APD-induced side effects in aged mice. Finally, we will evaluate the therapeutic benefits of HDACi and APD co-treatment that could reduce the severity of APD-induced side effects in aged mice and in Tg2576 mice, an animal model of Alzheimer's disease also being considered as a model of BPSD. The proposed study will advance our understanding of the mechanisms of age-related epigenetic alterations and their effects on APD action. This mechanistic concept will have implications not only for neuropsychiatric medication but also for other medications in geriatrics. Our study will serve as a guide to investigate epigenetic mechanisms on drug action with ultimate benefiting for the aged population.
描述(由申请人提供):为老年人开出的一类常见药物,用于治疗精神疾病以及痴呆症的行为和心理症状(BPSD)。然而,在老年患者中,副作用的发生率和严重程度,例如经历。 APD 引起的锥体外系运动症状增加,尽管年龄引起的药代动力学变化可能导致老年人对 APD 副作用的敏感性增加,但目标受体水平的年龄相关药效变化可能在增加中发挥关键作用。然而,对 APD 副作用的敏感性。
这些与年龄相关的受体功能下降的机制尚不清楚。最近,我们发现组蛋白修饰改变了典型 APD(氟哌啶醇)对老年小鼠的治疗作用。此外,我们在本申请中的初步数据表明,组蛋白修饰会改变老年小鼠的治疗作用。老年小鼠锥体外系症状样副作用(运动副作用)的严重程度可能与多巴胺 2 受体 (D2R) 基因 (Drd2) 启动子的组蛋白低乙酰化有关,从而降低了与组蛋白脱乙酰酶抑制剂 (HDACis) 丙戊酸 (VPA) 或恩替司他 (MS-275) 联合治疗可恢复纹状体 D2R 的表达,并减少氟哌啶醇与年龄相关的运动副作用的增加。表明目标受体基因启动子上与年龄相关的组蛋白修饰可能影响 APD 作用。在本提案中,我们试图确认调节背后的新表观遗传机制。衰老过程中 APD 的作用,并确定 HDACis 是否可以作为改善老年人 APD 治疗的候选者。我们的中心假设是,APD 的运动副作用与年龄相关的增加是由于其目标受体基因上的组蛋白低乙酰化所致。表观遗传变化及其功能后果可以通过与 HDACis 联合治疗来逆转。为了检验我们的假设,首先,我们将验证年龄相关的组蛋白修饰是对 APD 引起的副作用敏感性增加的机制之一。将要最后,我们将评估 HDACi 和 APD 联合治疗的治疗效果,以减轻 APD 诱导的严重程度。老年小鼠和 Tg2576 小鼠(一种阿尔茨海默病动物模型,也被认为是 BPSD 模型)的副作用这项拟议的研究将增进我们对与年龄相关的表观遗传改变的机制及其对 APD 的影响的理解。这一机制概念不仅对神经精神药物产生影响,而且对老年医学中的其他药物也产生影响。我们的研究将作为研究药物作用的表观遗传机制的指南,最终使老年人受益。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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Hongxin Dong其他文献
Hongxin Dong的其他文献
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{{ truncateString('Hongxin Dong', 18)}}的其他基金
Epigenetic Regulation in Aging and Alzheimer's Disease
衰老和阿尔茨海默病的表观遗传调控
- 批准号:
10564831 - 财政年份:2022
- 资助金额:
$ 38.63万 - 项目类别:
Molecular Mechanisms Underlying Behavioral and Psychological Symptoms in Alzheimers Disease
阿尔茨海默病行为和心理症状的分子机制
- 批准号:
10452490 - 财政年份:2018
- 资助金额:
$ 38.63万 - 项目类别:
Molecular Mechanisms Underlying Behavioral and Psychological Symptoms in Alzheimers Disease
阿尔茨海默病行为和心理症状的分子机制
- 批准号:
9788262 - 财政年份:2018
- 资助金额:
$ 38.63万 - 项目类别:
Molecular Mechanisms Underlying Behavioral and Psychological Symptoms in Alzheimers Disease
阿尔茨海默病行为和心理症状的分子机制
- 批准号:
10183128 - 财政年份:2018
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$ 38.63万 - 项目类别:
Sex differences in central stress response and Alzheimer's disease neuropathology
中枢应激反应和阿尔茨海默病神经病理学的性别差异
- 批准号:
9924147 - 财政年份:2017
- 资助金额:
$ 38.63万 - 项目类别:
Age-Related Histone Modification Effect on Antipsychotic Action
年龄相关的组蛋白修饰对抗精神病作用的影响
- 批准号:
9077000 - 财政年份:2016
- 资助金额:
$ 38.63万 - 项目类别:
Aging and Antipsychotic Efficacy - Epigenetic Mechanisms
衰老和抗精神病药的功效——表观遗传机制
- 批准号:
8600189 - 财政年份:2012
- 资助金额:
$ 38.63万 - 项目类别:
Aging and Antipsychotic Efficacy - Epigenetic Mechanisms
衰老和抗精神病药的功效——表观遗传机制
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8445889 - 财政年份:2012
- 资助金额:
$ 38.63万 - 项目类别:
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