Pharmacological targeting of circadian clock components to treat glioblastoma

项目摘要。 此行政补充请求是针对NOT-AG-20-034，阿尔茨海默病患者S提出的 NIH不专注于阿尔茨海默氏症的行政补助。昼夜节律紊乱 节奏和睡眠，长期以来被认为是阿尔茨海默病和相关痴呆症(ADRD)的症状， 越来越被认为是疾病发生和发展的早期贡献者。这可能是由 生物钟在维持大脑内环境平衡功能中的作用。在分子水平上，昼夜节律 时钟成分与参与体内平衡调节的基因的转录调节有关 能量平衡，活性氧产生，神经炎症，蛋白平衡，蛋白质分泌， 突触功能，神经元、星形胶质细胞和胶质细胞的管家功能。与年龄相关的抑制 生物钟可能会增加ADRD的风险。相反，行为或药理学方法可以促进 昼夜节律或时钟成分的功能是管理ADRD的新策略。 我们的研究团队提供了使用第一代药理学工具的第一个概念证明 靶向生物钟成分REV-ERBα和β(NR1D1和NR1D2)的小鼠模型 阿德勒。每天服用REV-ERB激动剂SR9009有效地降低了疾病的严重性，因为 行为测试的改善和聚集物的减少证明了这一点。然而，有一些主要的 知识差距-这种第一代药物在AD小鼠模型上的分子作用模式尚不清楚， 迫切需要开发下一代具有更好药理作用的REV-ERB激动剂 特点和效力。请拨的这笔补充资金将用于(A)确定行动模式 (B)筛选新的REV-ERB激动剂以提高细胞内的疗效。 基础化验。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疾病严重性中的作用和新化学实体的发现 改善神经元的药理特性。通过补充预算取得的这些关键成果 将为未来的研究奠定基础，开发针对生物钟的新化合物来治疗 阿德勒。

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.