Date of Award

January 2021

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Btian Hafler

Abstract

Neurodegeneration occurs in a plethora of diseases, including age-related macular degeneration (AMD), Alzheimer Disease (AD), and multiple sclerosis (MS), each with distinct inciting events and significant glial components. To determine whether glial transcriptional states are shared across phases of degeneration, we sequenced 50,498 nuclei from the retinas of seven AMD patients and six healthy controls, generating the first single-cell transcriptomic atlas of AMD. We identified groupings of cells implicated in disease pathogenesis by applying a novel topologically-inspired machine learning approach called ‘diffusion condensation.’ By calculating diffusion homology features and performing persistence analysis, diffusion condensation identified activated glial states enriched in the early phases of AMD, AD and MS as well as an AMD-specific proangiogenic astrocyte state promoting pathogenic neovascularization in advanced AMD. Finally, by mapping the expression of disease-associated genes to glial states, we identified key signaling interactions mediated by these glial states, and thus creating hypotheses for therapeutic intervention. Our multigranular analysis identified an integrated disease-phase specific glial landscape that is shared across neurodegenerative conditions affecting the central nervous system.

Comments

This thesis is restricted to Yale network users only. This thesis is permanently embargoed from public release.

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