Pharmacological targeting of circadian clock components to treat glioblastoma

项目摘要。 本行政补充申请是为了响应NOT-AG-20-034，以阿尔茨海默病为重点的 美国国立卫生研究院赠款的行政补充，不集中在阿尔茨海默氏症。昼夜节律紊乱 节律和睡眠，长期以来被认为是阿尔茨海默病和相关痴呆症（ADRD）的症状， 越来越多地被认为是疾病发作和进展的早期因素。这可能是因为 生物钟在维持大脑自我平衡功能中的作用。在分子水平上，昼夜节律 生物钟成分与基因的转录调控有关，这些基因参与了 能量平衡，活性氧产生，神经炎症，蛋白质稳态，蛋白质分泌， 突触功能，神经元、星形胶质细胞和神经胶质的管家功能。与电子邮件有关的 生物钟可能增加ADRD的风险。相反，行为或药理学方法，以提高 昼夜节律或生物钟成分的功能是管理ADRD的新策略。 我们的研究团队提供了第一个使用第一代药理学工具的概念验证 靶向生物钟成分REV-ERB α和β（NR 1D 1和NR 1D 2）， ADRD。每日施用REV-ERB激动剂SR9009有效地降低了疾病的严重程度， 通过行为测试的改善和α-淀粉样蛋白聚集体的减少来证明。然而，有一些主要的 知识空白-这种第一代药物对AD小鼠模型的分子作用模式尚不清楚， 迫切需要开发下一代REV-ERB激动剂， 特点和潜力。所请求的补充资金将用于：（a）描述行动模式 和（B）筛选新的REV-ER B激动剂以改善在细胞中的功效。 基于分析。拟议实验的完成将为REV的作用模式提供新的见解- ERB化合物在减轻ADRD疾病严重程度中的作用以及新的化学实体的发现 改善神经元的药理学特性。这些关键的结果获得了补充预算 将为未来的研究奠定基础，以开发针对生物钟的新型化合物， ADRD。

Project Summary. This request for an administrative supplement is submitted in response to NOT-AG-20-034, Alzheimer' s-focused administrative supplements for NIH grants that are not focused on Alzheimer's disease. Disruption of circadian rhythm and sleep, long considered to be a symptom of Alzheimer's Disease and related dementia (ADRD), is increasingly recognized as an early contributor to disease onset and progression. This may be explained by the role of the circadian clock in maintaining the homeostatic function of the brain. At the molecular level, circadian clock components are linked to transcriptional regulation of genes implicated in the homeostatic regulation of energy balance, reactive oxygen species production, neuroinflammation, proteostasis, protein secretion, synaptic function, housekeeping functions of neurons, astrocytes, and glia. Age-related dampening of the circadian clock may increase the risk for ADRD. Conversely, behavioral or pharmacological approaches to boost circadian rhythm or function of clock components are novel strategies to manage ADRD. Our research team has provided the first proof-of-concept of using the first-generation pharmacological tool targeting the circadian clock components REV-ERB alpha and beta (NR1D1 and NR1D2) in a mouse model of ADRD. Daily administration of the REV-ERB agonist SR9009 effectively reduced the disease severity as evidenced by improvement in behavioral tests and reduction in a aggregates. However, there are major knowledge gaps- the molecular mode of action of this first-generation drug on the AD mouse model is unknown, and there is an urgent need to develop the next generation REV-ERB agonists with improved pharmacological characteristics and potency. This supplemental fund requested will be used to (a) characterize the mode of action of SR9009 in the brain of mouse AD model and (b) screen novel REV-ERB agonists for improved efficacy in cell- based assays. Completion of the proposed experiments will offer new insight into the mode of action of REV- ERB compounds in alleviating the disease severity of ADRD and the discovery of new chemical entities with improved pharmacological properties in neurons. These critical results obtained with the supplemental budget will form the foundation for future research to develop novel compounds targeting the circadian clock to treat ADRD.