Author ORCID Identifier
0000-0002-6933-0927
Date of Graduation
8-2024
Document Type
Dissertation (PhD)
Program Affiliation
Biochemistry and Cell Biology
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Seung-Hee Yoo, PhD
Committee Member
Zheng Chen, PhD
Committee Member
Rodrigo Morales, PhD
Committee Member
John O'brien, PhD
Committee Member
Hyun Kyoung Lee, PhD
Abstract
The mammalian circadian clock responds to the 24-hour daily cycle and regulates tissue-specific gene expression and downstream physiology. The central pacemaker located in the hypothalamic suprachiasmatic nuclei (SCN) synchronizes the peripheral clocks in different tissues. This dissertation aims to uncover specific circadian regulatory mechanisms in the brain and skeletal muscle.
Alzheimer’s Disease (AD) is the most common type of dementia. It has previously been shown that there is a strong correlation of disease progression with circadian rhythm decline. We showed that circadian modulation by a small molecule Nobiletin (NOB) was able to mitigate AD pathogenesis. Furthermore, NOB significantly alleviated the strong neuroinflammation and astrogliosis in AD model APP/PS1 mice. NOB also significantly improved glucose utilization and insulin signaling in these mice. Furthermore, I report initial evidence for a possible NOB-ROR downstream mechanism through Ephrin signaling and the NF-κB pathway.
We also investigated the circadian regulation in the skeletal muscle through FBXL21-mediated TCAP degradation. Psttm, or FBXL21 loss of function mutant, affected TCAP oscillation and inhibited TCAP degradation. GSK-3β acts as an upstream kinase regulating TCAP degradation and activating FBXL21 E3 ligase function. This regulation was impaired in Psttm mice, and leading to reduced skeletal muscle output function.
This dissertation highlights a critical role of circadian regulation for tissue health and disease intervention.
Keywords
Circadian Rhythms, Alzheimer's Disease, Neuroinflammation, Skeletal Muscle Physiology, Nobiletin, Ubiquitination, FBXL21, TCAP
Included in
Biochemistry, Biophysics, and Structural Biology Commons, Cognitive Neuroscience Commons