Leung, Alex Chung Man; (2023) Single Cell Expression Analysis for Understanding the Development of Glaucoma. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Glaucoma is characterized as a group of eye diseases where the progressive damage of neurons, particularly Retinal Ganglion Cells (RGCs), leads to vision loss. This disease affects more than 70 million people worldwide, with approximately 10% being bilaterally blind, making it the leading cause of irreversible blindness in the world. The initiation and progression of the disease is still unknown, but studies have suggested the involvement of particular cell types in the retina that relate to the pathogenesis of glaucoma. Single cell RNA sequencing (RNA-seq) analysis is a new technology that provides insight into the gene expression profiles of different cell types. In this study, we employed it to elucidate the transcriptomic changes in various cell types during glaucoma progression. ABCA1-/- mice were used as a normal tension glaucoma model. Single cell RNA-seq experiments were conducted on three wild type (WT) and five knockout (KO) retinal tissues. The data of 62,479 cells were integrated and major cell types were identified, including Müller glia, astrocytes, microglia and RGCs. Ontological analysis suggested strong activation of neuroinflammation and senescence related pathways in KO samples, with specific pathways identified affecting certain cell types. Evidence of macrophage invasion further suggests a knockout-induced inflammatory response, accompanied by sub-type specific RGC degeneration due to excitotoxicity. P2Y6-/- mice were used as a high intraocular pressure (IOP) glaucoma model. 105,772 cells from three WT and three KO retinal tissues were analysed using single cell RNA-seq, with major cell types identified such as RGCs and glial cells. Neuroinflammation and senescence pathways activation was again observed, along with angiogenesis, hypoxia and fibrosis activities activated in knockout glial population. pathogenesis, thus provided data to support future interests in developing potential therapeutical targets in the area. pathogenesis, thus provided data to support future interests in developing potential therapeutical targets in the area.

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