Saudi Cultural Missions Theses & Dissertations
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Item Restricted EXPLORING THE ROLE OF BRAIN ANGIOGENESIS INHIBITOR 3 (BAI3) IN REGULATING BODY WEIGHT(The University of Alabama at Birmingham, 2024) a. Alsharif, Haifa; Bhatnagar, SushantObesity is a significant public health issue, strongly associated with various metabolic disorders, including type 2 diabetes and cardiovascular disease. Understanding the mechanisms that contribute to obesity is essential for developing effective interventions. One critical area of interest involves G-protein-coupled receptors (GPCRs), which are important in regulating metabolic health. These receptors are known to be involved in critical metabolic functions such as insulin secretion, lipid metabolism, and glucose uptake. The role of the GPCR, brain angiogenesis inhibitor-3 (BAI3), in metabolic regulation has not been fully explored. This dissertation focuses on the known functions of the BAI isoforms (BAI1-3) and presents a novel perspective on how BAI3 may influence whole-body glucose homeostasis. Specifically, I investigate the role of BAI3 in regulating body weight. I hypothesize that BAI3 controls body weight by regulating energy expenditure. To test this, I utilized a whole-body BAI3 knockout model and discovered that BAI3 influences energy expenditure through adaptive thermogenesis in young mice, independent of sex. Building on these findings, I expanded our study to examine how the loss of BAI3 affects diet-induced obesity (DIO) in the context of a high-fat diet (HFD) and its associated metabolic consequences. Genetic studies have linked BAI3 to alterations in body mass index (BMI) and various metabolic traits, and it is known to mediate cAMP inhibition. Based on this, I hypothesize that BAI3 negatively regulates energy balance, potentially worsening overall metabolic health. A series of experiments were conducted to test this hypothesis, and the results highlight BAI3 as a promising target for further investigation into energy homeostasis and metabolic regulation. Future studies should aim to delineate the specific signaling pathways involved in BAI3's metabolic effects and explore the potential for clinical applications of BAI3 modulation in improving metabolic health.5 0Item Embargo Spatial Organization of Metabolic and Signalling Systems(Imperial College London, 2024-06) Almutairi, Abdulrahman; J, KrishnanSingle cells utilize spatial organization through different mechanisms: localizing proteins in compartments, in subdomains in the compartments, or by creating concentration gradients. It generates an intricate web of connections in time and space, allowing living creatures to adapt to different environments. Understanding the effect of spatial organization requires a systematic assessment of the interplay of pathways and spatial organization. In this work we analyze both metabolic and signalling systems, starting with their constituent building blocks. A systematic assessment of spatial localization and compartmentalization with its impact on metabolic networks was evaluated. (i) The effect of localization of enzymes and substrates on a variety of metabolic motifs was assessed. (ii) The impact of spatial localization on standard metabolic control coefficients was evaluated and complemented with the inclusion of newly defined spatial control coefficients. (iii) The use of localization for rewiring metabolic networks and the unraveling of various trade-offs therein. (iv) The effect of localization in a concrete exemplar case was evaluated. Then for signalling systems, both enzymatic cascades and substrate modification were evaluated by studying compartmental systems and examining the effect of transport in the spatially. Basic motifs and network motifs were evaluated, while studying the effect of distribution in multiple compartments. Lastly, spatial feedbacks, wherein species either activated or inhibited their transport were defined and evaluated. Our results provide a number of new insights. Common recurring conclusions include the fact that spatial organization can rewire/alter reactions and networks, open up trade-offs depending on the choice of compartmentalized entities, and even generate non-trivial dynamic behaviours. All of this has shown that considering the spatial aspect adds an interesting and intricate twist to the behaviour of biological systems providing a powerful new way to engineer them. These insights can be utilized to optimize, design and engineer robust systems for clear objectives.18 0Item Restricted Probing Metabolic Pathways using an RccR Based Genetically Encoded Biosensor(Saudi Digital Library, 2023-11-24) Babtain, Ahmad; Dixon, NeilThe study of metabolic pathways is of utmost importance to contemporary biotechnology. However, mapping metabolic pathways is a burdensome process due to the entangled and complex nature of biological systems. Due to the direct involvement of transcription factors in metabolism, biosensors based on them are a powerful tool for researching metabolism. In this study, we used a biosensor vector where the RccR transcription factor regulates the expression of eGFP in response to the metabolite KDPG to investigate the central metabolism of two bacterial species of high relevancy to biotechnology: Pseudomonas Putida and Escherichia Coli, with an experimental focus on the first. Our research demonstrates that acetate, aromatic acids, and fatty acids enter the central metabolism of P. Putida through the TCA cycle. We also show among the aromatic acid, PCA and benzoic acid flux into central metabolism through one metabolic intermediate through a pathway with moderately low metabolic leakage. On E. Coli’s end, we show that acetate and the fatty acid C18:2 enter metabolism through the TCA cycle as well. We also employ bioinformatic databases to show that HexR is closely related to RccR and that the differences between the HexR proteins in P. Putida and E. Coli might show differing interference with RccR’s function. Our results also indicate that P. Putida preferentially consumes glucose, then acetate, and then aromatic acids when presented with mixtures of them. Finally, we saw strong evidence of the presence of a metabolic pathway that leads from acetate into the central metabolism of E. Coli. through acetyl-CoA.24 0Item Restricted NAD+ and the metabolism of cellular glucocorticoids in Endoplasmic Reticulum(Saudi Digital Library, 2023-12-01) Kabli, Ali; Lavery, GarethNicotinamide Adenine Dinucleotide (NAD+) has a primary role in cellular metabolism and energy production as a cofactor for a set of enzymatic reactions. The endoplasmic reticulum (ER) lumen enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) obtains NADPH from hexose-6-phosphate dehydrogenase to reduce cortisone to the active glucocorticoid cortisol. Cells depleted in NAD+ (parent molecule of NADPH) have impaired 11β-HSD1 activity, which can be rapidly rescued with supplementation of the NAD+ precursor nicotinamide riboside (NR). This suggests the existence of an ER-specific pathway to NAD(P)(H). Here we depleted cellular NAD+ using FK866 (NAMPT inhibitor) and poly-ADP-ribose assisted protein localization assay to study ER-specific NAD+ metabolism using 11β-HSD1 as a readout. To assess the generalizability of our results, we examined the enzyme activity in multiple cell types such as liver, muscle, dermal fibroblast, and human kidney. Results show preliminary evidence that depleting ER NAD+ can impair NADPH-dependent 11β-HSD1 activity. Repleting NAD+ availability with NR treatment significantly rescued the enzyme activity. Further experiments are required to thoroughly evaluate the potential of a dynamic NAD(P)(H) pathway in the ER compartment.9 0Item Restricted Assessing metabolic profiling for personalised nutrition(Saudi Digital Library, 2023-09-27) Alqarni, Lina; Frost, GaryBackground: Non-communicable diseases (NCDs) are the main causes of mortality and morbidity, globally and in the UK. Dietary changes, such as increasing intake of fibre, fruits and vegetables and reducing intake of saturated fat, free sugar and salt, have shown positive impacts on the risk factors associated with NCDs. However, there are concerns about the effectiveness of general dietary advice, due to the ineffectiveness in motivating people to change their eating habits or differences in individual biological responses to dietary intakes. Personalised dietary advice is proposed as an effective approach when considering the differences in individual response to diet and can be a more proactive intervention when it comes to encouraging people to change their eating habits. Recent advances have been made in the development of a new methodology that uses metabolic profiling and multivariate mathematical modelling to provide objective, accurate information about an individual's dietary patterns based on urine composition, which can be used to design personalised nutritional interventions. The aim of the thesis is to assess the feasibility of translating the metabolic profiling strategy into clinic to improve the nutritional management in the prevention of NCDs, including cardiovascular disease (CVD), by objectively assessing dietary habits and monitoring the compliance to dietary recommendations in order to provide personalised nutritional advice. Methods: Data from a previous pilot study was used to investigate concordance between metabolic profiling and traditional methods on long term dietary assessment in order to assess accurate dietary intakes. In a highly controlled environment, a randomised inpatient crossover clinical trial was conducted to assess the impact of dietary interventions on urinary metabolic profiles and clinical parameters in order to build a new mathematical model, particularly for people at risk of CVD. A dietary protocol was developed to facilitate personalised dietary counselling in alignment with public and patient involvement. A randomised pilot clinical trial was conducted to assess the feasibility of providing metabolically personalised dietary advice in clinic to help people at risk of CVD to change their dietary habits within their own environment using the new mathematical model and dietary protocol. Results: Findings from the pilot study showed poor agreement between the DASH score and the urinary dietary patterns score in overall data and subgroups. There were discrepancies in the concordance between the classifications of the dietary adherence of the urinary biomarkers and their related dietary intakes. In the randomised inpatient trial, two distinct isoenergetic dietary interventions with different compliance levels to NICE dietary guidelines were designed. Significant differences in the dietary intakes between the interventions (Diet1 vs Diet2) were reflected in the urinary metabolic profiles of participants; the RM-MCCV-PLS-DA model shows clear separation in the global urinary metabolic profiles of the two dietary patterns. A robust model has been developed using the global urinary metabolic profile associated with distinct dietary patterns. A dietary protocol has been developed to facilitate personalised dietary counselling and this was in alignment with public and patient involvement (PPI). PPI has positively impacted our dietary intervention design, researchers, dietitians, and participants at risk of CVD who involved in PPI activities. Finally, the randomised pilot clinical trial shows the feasibility of using metabolic profiling in clinic to personalise dietary advice for people at risk of CVD. Conclusion: A metabolic profiling strategy is promising and feasible and can objectively provide information about dietary adherence. In addition, it can be applied in conjunction with traditional dietary assessment methods to obtain further details about individual diets. However, some considerations need to be taken when applying urinary metabolic profiles in personalise nutrition and further research is needed to enhance the application of urinary metabolic profile.10 0