Saudi Cultural Missions Theses & Dissertations
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Item Restricted The Impact Of Dilated Cardiomyopathy on Cell-Type Diversity and Gene Expression(The University of Manchester, 2024) Alammari, Eman; Eales, James; Eales, JamesBackground: Dilated cardiomyopathy (DCM) is a leading cause of heart failure characterised by enlarged ventricles and reduced cardiac function. Despite advancements, understanding the cellular and molecular processes related to DCM remains challenging. Objectives: This study uses single-cell transcriptomics to identify unique gene expression patterns and cellular diversity in DCM to improve patient stratification and clinical care. Methods: Publicly available single-cell RNA sequencing (scRNA-seq) and single-nucleus RNA sequencing (snRNA-seq) data from normal cardiac tissues and DCM patients were obtained from the GEO dataset GSE183852. The analysis included 269,794 samples from 45 participants, comprising 36,488 DCM cells, 66,669 DCM nuclei, 12,554 healthy cells, and 154,083 healthy nuclei. Data analysis involved quality control, normalisation, data integration, dimensionality reduction, clustering, DE analysis, and Gene set enrichment analysis (GSEA). Results: Principal component analysis identified 50 principal components. Unsupervised cluster annotation revealed 21 cell types in nuclei samples and 15 in cell samples. The analysis showed an underrepresentation of cardiomyocytes in the scRNA samples. Cell composition analysis demonstrated significant differences in cell type abundance between DCM and healthy tissues, including an increased ratio of fibroblasts in DCM and a decrease in cardiomyocytes. DE analysis identified several significant differentially expressed genes (DEGs), MYH6. DEGs were shown to overlap with well-known DCM genes from the PannelApp list. GSEA validated the enrichment of our genes in DCM-associated pathways; moreover, a strong trend of downregulation of many critical pathways was found across many cell types, including metabolic and energy pathways. Conclusion: Despite some limitations of single-cell technology in preserving certain cardiac cell types, the analysis revealed significant differences in cell type abundance and DE profile between healthy and DCM samples. This discovery of distinct gene expression patterns in DCM samples compared to healthy individuals presents potential diagnostic and therapeutic targets, offering hope for improved patient outcomes.6 0Item Restricted REPURPOSING DRUGS FOR HYPERCOAGULABLE CONDITIONS: A PRECISION MEDICINE APPROACH TO ADVANCE THERAPEUTIC DISCOVERY(Virginia Commonwealth University, 2024-12) Alghubayshi, Ali; Wijesinghe, Dayanjan SBackground: Sickle Cell Disease (SCD) and related hypercoagulable conditions, particularly those associated with elevated von Willebrand factor (vWF) levels, pose significant health challenges globally, with a notable burden in Saudi Arabia. Despite known genetic factors influencing these conditions, effective treatment options remain limited. This dissertation aims to leverage genomic data and bioinformatic techniques to identify novel therapeutic targets and drug repurposing opportunities for SCD and vWF-linked hypercoagulability. Methods: This research comprises three interconnected studies. First, a case-control Genome-Wide Association Study (GWAS) was conducted comparing Saudi SCD patients with healthy controls. The second study utilized bioinformatic pipelines to analyze the druggability of the identified genes that characterize Saudi SCD patients. The interaction of these genes with the currently approved medications was estimated. The third study extended this approach to vWF-linked hypercoagulability, utilizing publicly available GWAS data. These analyses integrated data from various sources, including databases of drug-gene interaction and protein structures, to identify potential drug repurposing candidates and novel drug targets. Results: The initial GWAS identified numerous significant genetic variants characterizing SCD cases in the Saudi population. Building on these findings, the second study revealed several approved medications showing potential for repurposing in SCD. Notably, drugs such as simvastatin, allopurinol, and specific immunomodulators have emerged as promising candidates. The analysis also identified novel drug targets with high druggability scores, in particular, the olfactory receptor gene clusters. The third study, focusing on vWF-linked hypercoagulability, identified additional potential candidates, including nebivolol, pravastatin, riociguat, candesartan, and acetylcysteine. This study also revealed several novel, highly druggable targets implicated in key processes related to blood coagulation and vascular function, such as CLEC4M and SLC44A2. Conclusion: This research provides a comprehensive framework for drug repurposing and novel drug discovery in SCD and related hypercoagulable conditions. The findings underscore the potential of leveraging genetic data to identify targeted therapies, offering a pathway to more personalized and likely effective treatments. While promising, these computational predictions require further validation through conducting clinical studies to be translated into clinical practice.24 0