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SPATIOTEMPORAL PROFILING OF GENE EXPRESSION IN HEALTH AND DISEASE

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Abstract

Advances in single-cell RNA sequencing and spatial transcriptomics have transformed our understanding of cell biology, allowing for the study of gene expression at the single-cell level within the context of tissue architecture. Here, I leverage the power of these technologies to investigate three critical biological processes: cardiac development, viral myocarditis, and ovulation. First, we combine spatiotemporal transcriptomics with data integration algorithms to study the development of the chicken heart. By spatial mapping of cellular differentiation trajectories, we reveal transcriptional differences between epithelial and mesenchymal cells in the epicardial lineage to uncover an intricate interplay between cellular differentiation and morphogenesis. Using spatially resolved expression analysis, we report anatomically restricted expression of extracellular matrix-associated genes and genes implicated in congenital heart disease. Shifting our focus to viral myocarditis, a leading cause of sudden death in children and young adults, we investigate the temporal, spatial, and cellular heterogeneity of host-virus interactions and spatially confined cell-cell interactions linked to reovirus infection in neonatal mice. We report cytotoxic T cell-mediated pyroptotic cell death of infected endothelial cells in the myocarditic heart, thus elucidating the pathogenesis of reovirus-induced myocarditis. To broaden our perspective and explore new frontiers, we then employ single-cell transcriptomics to explore the poorly understood genesis of villus smooth muscle cells in the intestine. We identify a local hierarchy of subepithelial fibroblast progenitors, including an intermediate myofibroblast-like cell phenotype, that progress to form and renew mature smooth muscle fibers throughout life, thus paving the way for new strategies to accelerate recovery of digestive function. Lastly, we investigate the effects of blocking calcium-release activated calcium channels with BTP2 in human peripheral blood mononuclear cells stimulated with the mitogen phytohemagglutinin (PHA). By examining immunoregulatory genes, we observe a shift towards immune tolerance and suggest a potential therapeutic value of BTP2 in autoimmune diseases and organ transplantation. Collectively, my work highlights the immense potential of single-cell and spatial transcriptomics in unraveling intricate biological processes in both health and disease contexts.

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Description

274 pages

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Date Issued

2023-08

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Keywords

Gene expression; Genomics; scRNA-seq; Single-cell genomics; Spatial transcriptomics; Transcriptomics

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Union Local

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Committee Chair

De Vlaminck, Iwijn

Committee Co-Chair

Committee Member

Danko, Charles
Parker, John

Degree Discipline

Computational Biology

Degree Name

Ph. D., Computational Biology

Degree Level

Doctor of Philosophy

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Government Document

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Attribution-NonCommercial-NoDerivatives 4.0 International

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dissertation or thesis

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