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ELEMENTS OF PHOTORECEPTOR HOMEOSTASIS:
INVESTIGATING PHENOTYPIC MANIFESTATIONS AND
SUSCEPTIBILITY TO PHOTORECEPTOR DEGENERATION IN GENETIC
KNOCKOUT MODELS FOR RETINAL DISEASE
by
Rosanne Marie Yetemian
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(GENETIC, MOLECULAR AND CELLULAR BIOLOGY)
August 2010
Copyright 2010 Rosanne Marie Yetemian
Object Description
| Title | Elements of photoreceptor homeostasis: investigating phenotypic manifestations and susceptibility to photoreceptor degeneration in genetic knockout models for retinal disease |
| Author | Yetemian, Rosanne Marie |
| Author email | yetemian@gmail.com; yetemian@usc.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Genetic, Molecular & Cellular Biology |
| School | Keck School of Medicine |
| Date defended/completed | 2010-05-26 |
| Date submitted | 2010 |
| Restricted until | Unrestricted |
| Date published | 2010-07-31 |
| Advisor (committee chair) | Craft, Cheryl M. |
| Advisor (committee member) |
Hinton, David R. Chen, Jeannie Sampath, Alapakkam P. Ma, Le |
| Abstract | G-protein coupled receptor kinase 1 (Grk1) is essential for light-activated opsin phosphorylation in phototransduction shutoff, and genetic defects cause Oguchi's disease, a form of Retinitis Pigmentosa (RP). To elucidate the recovery function of cone pigments, we combined Grk1-/- murine knockouts with the Neural retina leucine zipper (Nrl-/-), which have an enhanced S-cone phenotype. We observed that with increasing age and independent of light, the retinas of Nrl-/-Grk1-/- when compared to Nrl-/- developed progressive cone degeneration and decreased cone protein expression. The degeneration initially occurs in the central inferior quadrant and spreads with retinal pigment epithelia (RPE) atrophy. Endothelial cell specific immunohistochemistry and fluorescein angiography (FA) revealed progressive changes in retinal neovascularization in the Nrl-/-Grk1-/- at 1 month of age, prior to the onset of significant cone functional deficits and ONL thinning. Vascular Endothelial Growth Factor (VEGF) expression was also observed in the inner retina and within blood vessels at post natal (PN) 21 of these mice. To further delineate the cone degeneration phenotype, we performed microarray analyses, observed statistically significant changes in retinal transcript levels of >400 genes, and examined these candidates with Ingenuity Pathway Analysis (IPA). The Oncostatin M Signaling pathway was the top canonical pathway, and inflammatory disease/response genes were one of the top networks identified. These data demonstrate that the loss of a functional Grk1 on the Nrl-/- background exacerbates age-related cone dystrophy in a light-independent manner, mediated partly through the inflammatory response pathway leading to retinal neovascularization.; Our working hypothesis is that Grk1 ablation in cones leads to a hypoxic or metabolically compromised environment and subsequently stimulates increased blood vessel penetration into the retina, leading to increased inflammation and inevitable cone apoptosis. In addition to being essential for cone pigment recovery, Grk1 expression maintains a healthy cone environment and provides a model to examine potential cellular mechanisms of inherited disease associated with retinal angiogenesis such as Age-related Macular Degeneration (AMD). |
| Keyword | degeneration; knockout; photoreceptor; retina |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m3238 |
| Contributing entity | University of Southern California |
| Rights | Yetemian, Rosanne Marie |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | http://www.usc.edu/isd/libraries/services/ask_a_librarian/email/ |
| Filename | etd-Yetemian-3922 |
| Archival file | uscthesesreloadpub_Volume14/etd-Yetemian-3922.pdf |
Description
| Title | Page 1 |
| Contributing entity | University of Southern California |
| Full text | ELEMENTS OF PHOTORECEPTOR HOMEOSTASIS: INVESTIGATING PHENOTYPIC MANIFESTATIONS AND SUSCEPTIBILITY TO PHOTORECEPTOR DEGENERATION IN GENETIC KNOCKOUT MODELS FOR RETINAL DISEASE by Rosanne Marie Yetemian A Dissertation Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (GENETIC, MOLECULAR AND CELLULAR BIOLOGY) August 2010 Copyright 2010 Rosanne Marie Yetemian |
