The Role of Circadian Clock in the Embryonic and Post-Natal Development and Pathophysiology of Oral Tissues and Implications of Natural Treatments in Dental Caries Progression

The salivary glands (SGs) are exocrine glands that produce saliva and play crucial roles in maintaining oral and systemic health. Conditions such as Sjögren's syndrome, autoimmune disorders, and developmental malformations can lead to reduced salivary flow and alterations in saliva composition, resulting in symptoms such as dry mouth (xerostomia). The SG dysfunction not only affects oral health, leading to an increased susceptibility to dental caries, but also has potential systemic implications. The circadian clock, an endogenous intracellular mechanism, assumes a pivotal role in orchestrating physiological processes across various bodily organs including bone, teeth, and salivary glands. It is noteworthy that circadian mechanisms may also play a role in the development and aging of organs. Moreover, disruptions in circadian rhythm and clock gene expression have been associated with diverse pathological conditions, including autoimmune diseases and cancer. This growing body of evidence underscores the significance of the circadian clock in oral and systemic health, paving the way as a scientific target in the fields of oral sciences and chronodentistry. This Ph.D. thesis project is a comprehensive and multifaceted research initiative designed to explore the complex interrelationship between the circadian clock, SG development, and salivary function. Additionally, it aims to investigate the potential links between the circadian clock and SG diseases. The project also endeavors to evaluate preventive approaches to mitigate oral complications arising from SG malfunction, with a specific focus on preventing dental caries. In the initial phase of this thesis manuscript, an analysis of data from the 2017-2018 Canadian Community Health Survey was conducted to investigate various health outcomes linked to circadian clock with emphasis on associations with arthritis. Driven by its significant prevalence, impacting around one in five Canadians, the exploration of arthritis highlights its broad spectrum of associated health issues, including impacts on oral health, sleep quality, general health, and mental well-being. The study also delved into the impact of self-reported lifestyle factors on health outcomes, comparing individuals with and without arthritis. This cross-sectional examination revealed a noteworthy association between arthritis and health conditions, highlighting issues like sleep disturbances and oral health concerns such as dry mouth. Furthermore, the research underscored the influential role of lifestyle factors in shaping this relationship. Building upon the insights garnered in the initial phase, the second phase of the project was formulated and aimed to investigate the relationship between the circadian clock and SG diseases. Our focus centered on Sjögren's syndrome (SjS), a prevalent SG condition known for causing dry mouth. It is essential to note that SjS and some types of arthritis such as rheumatoid arthritis are autoimmune diseases, potentially displaying overlapping symptoms or concurrent diagnoses. We examined the differential expression of circadian clock genes and the relative levels of circadian proteins in the SGs of individuals with SjS or healthy controls and explored their correlations with the severity of the disease. The results showed a significant downregulation in the expression of circadian genes and proteins in individuals with SjS, and this downregulation was correlated with disease severity. These findings highlight the pivotal role of the circadian clock in the pathophysiology of SG disease. The results of the second phase paved the way for developing the third phase of this thesis. In this stage, our aim was to identify the impact of the circadian clock disruption on the development and functionality of SGs. Utilizing various circadian clock knock-out mice models, we examined the influence of circadian clock disruption on the developmental processes and maturation of SGs. Our investigations found no impact of circadian clock disruption on SG stem cells and related functional biomarkers in the prenatal stage but revealed significant postnatal effects on these biomarkers. These findings suggest that circadian clock disruption does not influence embryological-stage SG development but rather affects maturation and functionality postnatal. By integrating the findings from the previous phases, a noticeable correlation was found between the circadian clock and SG biology, along with observed changes in the expression of circadian clock genes in SjS. Furthermore, it highlighted the need for enhanced oral health care in individuals with autoimmune conditions affecting teeth and gums. These findings were used as a basis for developing the fourth phase of this project. Considering that dental caries is one of the most prevalent complications of dry mouth conditions, the objective of this phase was to evaluate the impact of suggested novel molecules on caries prevention. We have examined the efficacy of porphyrin molecules and tea tree oil in preventing caries and found that they significantly inhibited bacterial growth and reduced caries prevalence in a rat caries model. Additionally, these treatments enhanced tertiary dental formation response to caries progression. These findings not only indicate that such combination treatment holds promise for a novel approach in preventive dentistry and regenerative care but also serves as a stepping stone for subsequent investigations into the effects of these molecules on caries prevention in patients with xerostomia and poor oral health due to diseases and/or circadian clock disruption. In conclusion, this research illuminates the intricate interplay between the circadian clock, salivary gland development and diseases, and oral health, emphasizing the pivotal role of the circadian clock in orchestrating the physiological processes of SGs and its potential association with pathological conditions. The comprehensive and multifaceted nature of this research initiative also paves the way for promising preventive dental strategies through novel molecules and natural products. Additionally, it highlights the influential role of lifestyle modifications as integral components of enhanced general and oral care, underscoring the imperative for heightened oral care in autoimmune conditions. This holistic approach contributes to a deeper understanding of the intricate connections between circadian rhythms, salivary gland health, and overall oral well-being.

Name thesis:degree_name

Doctor of Philosophy (Ph.D.)

Level thesis:degree_level

Doctoral

Discipline thesis:degree_discipline

Health Sciences

Grantor

University of Saskatchewan

Year dc:date.issued

2024

Author dc:creator

• Hoja, Ibrahim

Advisors dc:contributor.advisor

• Katselis, George
• Papagerakis, Petros

Committee members dc:contributor.committeemember

• Lukong, Kiven
• Papagerakis, Silvana
• Lieffers, Jessica
• Liu, Juxin
• Tamimi, Faleh

• Circadian Clock, Salivary Glands, Emberyology, Stem Cells, Dental Caries, Sjogren's syndrome, Oral Health

Language dc:language.iso

en

Handle dc:identifier.uri

https://hdl.handle.net/10388/15594

OAI identifier oai:identifier

oai:harvest.usask.ca:10388/15594