Thesis (M.A.)--Boston University / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / Retinitis pigmentosa (RP) is a collection of inherited retinal degenerations that afflicts 50,000- 100,000 people in the United States. The hallmark pathology of RP is apoptosis of photoreceptor cells. Currently there is no treatment for this disease. The equivalent light hypothesis states that some RP mutations cause retinal degeneration by mimicking a continuous phototransduction signal. We tested this hypothesis in transducin knockout (TKO-/-) mice, deficient for the a - subunit of transducin, the heterotrimeric G-protein which mediates light signaling in photoreceptors. Methods: We used light microscopy to compare the retinal morphology of TKO-/- and wild-type (TKO+/+) mice: 1) exposed to continuous bright light, or 2) crossed with mice carrying three different rhodopsin mutations leading to retinal degeneration: A) Proline347Serine (P347S), B) Valine20Giycine, Proline23Histidine, Proline27Leucine (VPP), and C) Lysine296Giutamic acid (K296E). Results: We predicted two types of photoreceptor cell apoptosis: 1) signal-dependent mutants in which degeneration was blocked in the absence of transducin, and 2) signal-independent mutants, not affected by the presence or absence of transducin signaling. To our surprise,we found three classes of retinal degeneration: 1) the VPP triple mutant caused photoreceptor apoptosis, at the same rate, regardless of the presence or absence of a-transducin, 2) the P347S and K296E opsin mutants caused an accelerated rate of degeneration on the TKO -/- background as compared to on the TKO+/+ background, and 3) the damaging effects of continuous light were retarded on the null transducin background. These data support the equivalent light hypothesis as a mechanism for some, but not all forms of retinal degeneration. Thus, the cellular signal that triggers photoreceptor apoptosis can occur either upstream or downstream of transducin signaling. Classifying different types of mutations that lead to photoreceptor cell death will be important for determining effective therapies for different classes of human retinal degeneration. / 2999-01-01

published_or_final_version / abstract / Anatomy / Doctoral / Doctor of Philosophy

Thesis (Ph. D.)--University of Hong Kong, 2007. / Title proper from title frame. Also available in printed format.

Thesis (Ph. D.)--University of Sydney, 2008. / Title from title screen (viewed 18 June 2008). Submitted in fulfilment of the requirements for the degree of Doctor of Philosophy to the Department of Clinical Ophthalmology and Eye Health, Faculty of Medicine. Degree awarded 2008; thesis submitted 2007. Includes bibliographical references. Also available in print form.

Thesis (doctoral)--Lund University, 1998. / Added t.p. with thesis statement inserted. Includes bibliographical references.

Thesis (doctoral)--Lund University, 1998. / Added t.p. with thesis statement inserted. Includes bibliographical references.

Thesis (Ph. D.)--University of Washington, 2007. / Vita. Includes bibliographical references (leaves 91-101).

Indiana University-Purdue University Indianapolis (IUPUI) / Human pluripotent stem cells (hPSCs) have the ability to self renew indefinitely while maintaining their pluripotency, allowing for the study of virtually any human cell type in a dish. The focus of the current study was the differentiation of hPSCs to retinal ganglion cells (RGCs), the primary cell type affected in optic neuropathies. hPSCs were induced to become retinal cells using a stepwise differentiation protocol that allowed for formation of optic vesicle (OV)-like structures. Enrichment of OV like structures allowed for the definitive identification of RGCs. RGCs displayed the proper temporal, spatial, and phenotypic characteristics of RGCs developing in vivo. To test the ability of hPSC-RGCs to serve as a disease model, lines were generated from a patient with an E50K mutation in the Optineurin gene, causative for normal tension primary open angle glaucoma. E50K RGCs displayed significantly higher levels of apoptosis compared to a control lines. Apoptosis was reduced with exposure to neuroprotective factors. Lastly, hPSC-derived RGCs were studied for their ability to develop functional features possessed by mature in vivo RGCs. hPSC-derived RGCs displayed a few immature functional features and as such, strategies in which to expedite synaptogenesis using hPSC-derived astrocytes were explored. Astrocyte and RGG co-cultures displayed expedited synaptic and functional maturation, more closely resembling mature in vivo RGCs. Taken together, the results of this study have important implications for the study of RGC development and by extension, the advancement of translational therapies for optic neuropathies.

published_or_final_version / abstract / Anatomy / Doctoral / Doctor of Philosophy

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