THE ROLE of THE CIRCADIAN CLOCK IN DISEASE and TISSUE FUNCTION

<p>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.</p> <p>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. </p> <p>We also investigated the circadian regulation in the skeletal muscle through FBXL21-mediated TCAP degradation. <em>Psttm</em>, 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 <em>Psttm</em> mice, and leading to reduced skeletal muscle output function.</p> <p>This dissertation highlights a critical role of circadian regulation for tissue health and disease intervention.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2024

Authors dc:creator

• Wirianto, Marvin
• <p>0000-0002-6933-0927</p>

Contributors dc:contributor

• Seung-Hee Yoo, PhD
• Zheng Chen, PhD
• Rodrigo Morales, PhD

• Circadian Rhythms
• Alzheimer's Disease
• Neuroinflammation
• Skeletal Muscle Physiology
• Nobiletin
• Ubiquitination
• FBXL21
• TCAP
• Biochemistry, Biophysics, and Structural Biology
• Cognitive Neuroscience

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1380

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2437