Date of Award

Summer 8-2-2023

Embargo Period

8-5-2028

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Molecular and Cellular Biology and Pathobiology

Additional Department

Neuroscience

College

College of Graduate Studies

First Advisor

Bärbel Rohrer

Second Advisor

Hainan Lang

Third Advisor

Judy R. Dubno

Fourth Advisor

Carl Atkinson

Fifth Advisor

Shahid Husain

Sixth Advisor

Robin Muise-Helmericks

Abstract

Dual sensory loss is defined as a combination of age-related vision loss, e.g., age-related macular degeneration (AMD), and age-related hearing loss (ARHL), that co-occurs in people aged >65 years. Dry and wet forms of AMD and ARHL share etiologies such as smoking and complement dysregulation. Controlling the complement alternative pathway (AP) amplification loop is crucial, as it causes the majority of complement activation on cell surfaces and extracellular membranes. AP is inhibited by circulating complement protein factor H (fH). Additionally, natural antibodies (nAbs) binding to neoepitopes on damaged tissues in response to injury can activate complement. Complement effector molecules and nAbs have been shown to be elevated in the subretinal space of wet AMD, smoke-induced ocular damage, and the cochlear tissues of aged mouse models where they activate macrophages and intensify the inflammatory state leading to neurodegeneration. In this project, two well-studied fusion proteins, CR2-fH and B4-scFv-fH, were used to target the inhibitory domain of fH to damaged tissue. The complement receptor 2 (CR2) domain binds to complement fragments deposited on sites of inflammation, and the single chain antibody B4 (B4-scFv) domain binds to modified annexin IV exposed on damaged tissues. Mouse models of neurodegenerative diseases have shown both to be efficacious when administered systemically, locally, and via gene therapy (CR2-fH). Our study suggests that vector-driven CR2-fH and injected B4-scFv-fH localize fH to damaged nerve tissues and mitigate wet AMD and ARHL pathology by reducing macrophage activation and lessening the complement-macrophage inflammatory feedback loop.

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Copyright is held by the author. All rights reserved.

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Available for download on Saturday, August 05, 2028

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