M1 PAMs for Age-Related Cognitive Impairments
M1 PAM 用于治疗与年龄相关的认知障碍
基本信息
- 批准号:9919471
- 负责人:
- 金额:$ 66.67万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-08-01 至 2022-04-30
- 项目状态:已结题
- 来源:
- 关键词:20 year oldAcetylcholineAcetylcholinesterase InhibitorsAddressAdverse effectsAge-associated memory impairmentAgingAgonistAllosteric SiteAlzheimer&aposs DiseaseAlzheimer&aposs disease patientAriceptArousalAttentionBehavioralBinding SitesChemosensitizationClinical TrialsCognitionCognitiveDementiaDevelopmentDoseDose-LimitingElectroencephalographyEvaluationFemaleFutureGlutamate ReceptorGlutamatesHippocampus (Brain)Impaired cognitionImpairmentMeasuresMediatingMemoryMicrodialysisModelingMusMuscarinic Acetylcholine ReceptorMuscarinic Acetylcholine Receptor M3N-MethylaspartateNeurosciencesPeripheralPhysiologicalPlayPopulationProcessProsencephalonRegulationRisk FactorsRoleSeriesShort-Term MemorySignal TransductionSiteSleepSleep ArchitectureSleep DisordersSleep disturbancesSpecificityTechniquesTestingTherapeuticTimeUnited Statesacetylcholine receptor agonistage relatedagedanalogcholinergicclassical conditioningcognitive functioncognitive performancedonepezildrug discoveryefficacy studyextracellularglutamatergic signalinghuman old age (65+)in vivomaleneurotransmissionnonhuman primatenormal agingnovelnovel strategiesnovel therapeuticspositive allosteric modulatorpotential biomarkerpre-clinicalreceptorresponserestorationsexside effecttooltranslational studytransmission process
项目摘要
PROJECT SUMMARY
It is estimated that in the United States alone there will be nearly 70 million people over the age of 65 by the
year 2030. Yet, there remains a critical unmet need to understand and identify novel therapeutic strategies to
address age-related impairments in arousal, cognitive function, and sleep architecture. Agents such as
acetylcholinesterase inhibitors (AChEIs) that enhance overall cholinergic transmission or activate muscarinic
acetylcholine receptors (mAChRs) have been developed to ameliorate the loss of cognitive function in normal
aging and Alzheimer’s disease (AD) populations. Accumulating evidence indicates that enhancement of central
cholinergic neurotransmission through activation of the M1 mAChR subtype represents an exciting alternative
approach for the treatment of impairments in cognition, arousal and sleep observed in normal aging and AD.
M1 is co-localized with the NR1a subunit of the N-methyl-D-aspartate subtype of glutamate receptor (NMDAR).
Selective activation of M1 potentiates prefrontal cortical (PFC) and hippocampal NMDAR currents and
enhances both PFC- and hippocampal-mediated associative learning and memory functions. Recently we
successfully optimized a novel series of isoindolinone M1 positive allosteric modulators (PAMs), represented by
VU0453595, as an alternative strategy for the selective activation of M1. The discovery and characterization of
VU0453595 represents an unprecedented opportunity to characterize the impact of selective M1 potentiation
on cortical ACh neurotransmission and cognition, arousal and sleep dysfunction associated with normal aging
in preclinical species. In Aim 1, we will determine effects of VU0453595 alone and in combination with the
AChEI donepezil on cortical acetylcholine and glutamate neurotransmission using in vivo microdialysis
techniques in young and aged male and female mice. Next, we will examine effects of VU0453595 alone and
in combination with donepezil to ameliorate age-related impairments in cognition and sleep architecture in
aged male and female mice (Aim 2). Finally, in Aim 3 we will investigate whether selective activation of M1 by
VU0453595 ameliorates age-related impairments in cognition and sleep architecture in male and female aged
NHPs. Together, these translational studies across species will extend our understanding of age-related
cognitive dysfunction, a critical risk factor for later onset dementia and AD, and the potential role of M1
modulation for restoration of age-related impairments in cognition and sleep architecture.
项目概要
据估计,仅在美国,65岁以上的人口就将达到近7000万。
到 2030 年。然而,仍然存在一个未得到满足的关键需求,即了解和确定新的治疗策略,以
解决与年龄相关的觉醒、认知功能和睡眠结构障碍。
乙酰胆碱酯酶抑制剂(AChEI),增强整体胆碱能传递或激活毒蕈碱
乙酰胆碱受体(mAChR)已被开发用于改善正常人认知功能的丧失
越来越多的证据表明,老龄化和阿尔茨海默病(AD)人群的中枢功能增强。
通过激活 M1 mAChR 亚型进行胆碱能神经传递是一种令人兴奋的替代方案
治疗正常衰老和 AD 中观察到的认知、觉醒和睡眠障碍的方法。
M1 与谷氨酸受体 (NMDAR) 的 N-甲基-D-天冬氨酸亚型的 NR1a 亚基共定位。
M1 的选择性激活可增强前额皮质 (PFC) 和海马 NMDAR 电流,
增强 PFC 和海马介导的联想学习和记忆功能。
成功优化了一系列新型异吲哚酮M1正变构调节剂(PAM),代表为
VU0453595,作为选择性激活 M1 的替代策略的发现和表征。
VU0453595 代表了一个前所未有的机会来表征选择性 M1 增强的影响
与正常衰老相关的皮质乙酰胆碱神经传递和认知、觉醒和睡眠功能障碍
在临床前物种中,我们将确定 VU0453595 单独使用以及与 VU0453595 结合使用的效果。
使用体内微透析 AChEI 多奈哌齐对皮质乙酰胆碱和谷氨酸神经传递的影响
接下来,我们将单独检查 VU0453595 和 VU0453595 的效果。
与多奈哌齐联合使用可改善与年龄相关的认知和睡眠结构损伤
老年雄性和雌性小鼠(目标 2)最后,在目标 3 中,我们将研究是否通过选择性激活 M1。
VU0453595 改善男性和女性老年认知和睡眠结构中与年龄相关的障碍
这些跨物种的转化研究将共同扩展我们对年龄相关的理解。
认知功能障碍是迟发性痴呆和 AD 的关键危险因素,以及 M1 的潜在作用
调节以恢复与年龄相关的认知和睡眠结构损伤。
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)
专利数量(0)
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Carrie Kimberly Jones其他文献
Carrie Kimberly Jones的其他文献
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{{ truncateString('Carrie Kimberly Jones', 18)}}的其他基金
M1 PAMs for Age-Related Cognitive Impairments
M1 PAM 用于治疗与年龄相关的认知障碍
- 批准号:
9383610 - 财政年份:2017
- 资助金额:
$ 66.67万 - 项目类别:
M1 PAMs for Age-Related Cognitive Impairments
M1 PAM 用于治疗与年龄相关的认知障碍
- 批准号:
10160750 - 财政年份:2017
- 资助金额:
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Discovery of mAChR5 Modulators for Use in Rodent Models of Drug Addiction
发现用于啮齿类药物成瘾模型的 mAChR5 调节剂
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8880514 - 财政年份:2015
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M4 Positive Allosteric Modulators for the Treatment of Schizophrenia
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8071545 - 财政年份:2009
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M4 正变构调节剂治疗精神分裂症
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7699766 - 财政年份:2009
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M4 Positive Allosteric Modulators for the Treatment of Schizophrenia
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- 批准号:
8468210 - 财政年份:2009
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8269701 - 财政年份:2009
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