Pharmacological targeting of circadian clock components to treat glioblastoma

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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.