Saudi Cultural Missions Theses & Dissertations
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Item Restricted Regulation of the carotid body type-1 cell by lipid signalling pathways(University of Oxford, 2024-02-09) Alsahafi, Zaki; Buckler, Keith; Pandit, JaideepDespite several proposed theories, the precise mechanism underlying acute oxygen sensing in type-1 cells of the carotid body remains elusive. This thesis investigates the role of Gq- coupled receptors and PLC signalling molecules in the regulation of carotid body type-1 cells by utilizing Ca2+ measurements and single channel electrophysiology. This thesis investigates the involvement of these signalling molecules in hypoxia-induced [Ca2+]i rise and TASK channel inhibition in type-1 cells. In addition, this thesis examines the role of PLC signalling molecules in mediating the effects of metabolic poisons and volatile anaesthetics on TASK channels in type-1 cells. This thesis seeks to address the question as to whether there might be a common signalling pathway mediating all these effects. Specifically, it proposes that lipid signalling may ultimately be central to all these forms of TASK channel regulation. Following the general introduction and methods chapters, chapter 3 examines the effects of Gq- coupled receptors and PLC signalling molecules on the hypoxia-induced [Ca2+]i rise in type-1 cell. The results show that hypoxia-induced [Ca2+]i rise was sensitive to alterations in Gq-coupled receptors and PLC-signalling molecules, suggesting that these signalling molecules are involved in mediating the hypoxia-induced [Ca2+]i rise in type-1 cells. Chapter 4, further examines the role of these signalling molecules by looking at their effects on the activity of TASK channels in type-1 cells. This chapter presents novel findings demonstrating the involvement of PLC signalling molecules in mediating the hypoxic inhibition of TASK channels in type 1 cells. It proposes a model for acute oxygen sensing in these cells, incorporating findings from chapters 3 and 4. Chapter 5 examines the role of PLC signalling molecules in mediating the effects of metabolic inhibitors on TASK channels. Metabolic inhibitors are known to inhibit TASK channels in type-1 cells and other cell types. We further confirmed this and showed that these effects are not likely to be mediated by PLC-produced DAG. Chapter 6 examines the interactions between DAG and halothane on TASK channels in type-1 cells. We demonstrated that DiC8, a DAG analogue, induced a strong, reversible, and dose-dependent inhibition of TASK channels and inhibited the halothane-induced activation of these channels. These novel findings support the hypothesis that anaesthetics and endogenous ligands may compete for binding sites in sensitive proteins. In conclusion, this thesis presents novel findings on the role of Gq-coupled receptors and PLC signalling molecules in the regulation of carotid body type-1 cells and suggests that these signalling molecules are involved in mediating the responses of type-1 cells to various endogenous and exogenous stimuli. Additionally, it posits that PLC signalling molecules establish a connection between metabolic function and the modulation of TASK channels by hypoxia in type-1 cells.30 0Item Restricted Detection of Dysfunctional Breathing Using Structured Light Plethysmography(Saudi Digital Library, 2023-09-28) Alhuthail, Eyas; Coney, Andrew; Cooper, BrendanDysfunctional breathing (DB) is a term often used to describe irregularities of breathing in patients. In practice, the detection of DB is primarily subjective in nature, with focus on questionnaires and physical examination that can be influenced by personal judgment. Development of new techniques and approaches to allow the quantification of DB is required. This thesis introduced the use of Structured Light Plethysmography (SLP) in the detection of dysfunctional breathing and exploring the variability that exists in normal breathing patterns. SLP provides the assessment of tidal breathing pattern measures while allowing measurements to be made in different positions due to it being mobile and flexible. In the first study, SLP demonstrated reproducible results when repeated on different occasions. DB patterns present with changes in breathing patterns, and SLP correlated well with these, albeit some differences in rapid shallow breathing. The second study focused on the development of an entropy measurement that quantifies the variability in breathing patterns. Patients with a restrictive condition showed a more controlled breathing pattern, whereas in obstructive patients, the entropy varied with body position. The last study was focused on the assessment of changes in breathing patterns of post-COVID-19 patients from ward and ITU units compared to healthy subjects; this has shown a persistent mild restrictive pattern approximately 3 months after discharge without a significant change in the entropy of breathing, suggesting some long term effects of hospitalisation due to COVID-19. The overall outcome allowed for the use of SLP in different positions and demonstrated the ability to detect different breathing patterns and the suitability of entropy analysis to be applied to the data acquired, showing another measure of variability. With further investigation, analysis of the variability of breathing patterns may be an additional tool to help understand DB.38 0