Ablation of Retbindin, the Riboflavin Binding Protein, Exacerbates Retinal Degenerative Phenotypes in Mouse Models of Human Retinal Diseases
| dc.contributor.advisor | Naash, Muna I. | |
| dc.contributor.committeeMember | Al-Ubaidi, Muayyad R. | |
| dc.contributor.committeeMember | Conley, Shannon M. | |
| dc.contributor.committeeMember | Frishman, Laura J. | |
| dc.contributor.committeeMember | Roh, Jinsook | |
| dc.creator | Genc, Ayse Mine | |
| dc.creator.orcid | 0000-0001-5473-0082 | |
| dc.date.accessioned | 2020-06-04T02:32:20Z | |
| dc.date.created | May 2020 | |
| dc.date.issued | 2020-05 | |
| dc.date.submitted | May 2020 | |
| dc.date.updated | 2020-06-04T02:32:20Z | |
| dc.description.abstract | Retbindin (Rtbdn) is a retina-specific, riboflavin binding protein, expressed only by the rod photoreceptor cells. Riboflavin is the precursor of flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) which are essential co-factors for enzymes involved in wide-range of metabolic processes. Since flavins are directly linked to the metabolism and metabolic dysregulation is a hallmark of degeneration, we hypothesized that Rtbdn, as a riboflavin binding protein, plays a role in modulating the degenerative process. In support of our hypothesis, we found that Rtbdn is significantly upregulated in the retinas of mouse models of late-onset cone rod dystrophy (Prph2R172W), retinitis pigmentosa (RhoP23H/+) and pattern dystrophy (Prph2Y141C/+). We investigated the effect of Rtbdn ablation in these retinal degenerative models in order to elucidate the function of this novel protein in retinal health and disease. Although, the ablation of Rtbdn alone (Rtbdn-/-) had no deleterious effects on retinal function up to postnatal day (P) 120, eliminating Rtbdn in the models led to significant reductions in both scotopic and photopic electroretinographic amplitudes, compared to the single mutants. Histologic assessments revealed severe thinning of diseased retinas upon elimination of Rtbdn. While the outer nuclear layer (ONL) cell counts in wild type (WT) and Rtbdn-/- were not significantly different from each other, we observed significant loss of ONL cells in the Prph2R172W/Rtbdn-/-, RhoP23H/+/Rtbdn-/-, and Prph2Y141C/+/Rtbdn-/- in comparison to the single mutants. Ultrastructural analyses revealed shorter, malformed and disorganized photoreceptor outer segments, swollen inner segments and dilated Bruch’s membrane in the retinas of degenerative models in absence of Rtbdn. In addition, elimination of Rtbdn in the diseased retina led to vascular pathologies and appearance of neovascular tufts secondary to cell loss. We observed model-dependent alterations in the riboflavin, FAD, and FMN levels. Our data demonstrate the potential protective role of Rtbdn, making it a strong candidate as a therapeutic target in retinal degenerative diseases. Our future work will focus on investigating that potential by studying the effects of overexpression of Rtbdn in slowing the retinal degenerative process in models of human retinal degeneration. | |
| dc.description.department | Biomedical Engineering, Department of | |
| dc.format.digitalOrigin | born digital | |
| dc.format.mimetype | application/pdf | |
| dc.identifier.citation | Portions of this document appear in: Ayse M. Genc, Mustafa S. Makia, Tirthankar Sinha, Shannon M. Conley, Muayyad R. Al-Ubaidi and Muna I. Naash,Elimination of a retinal riboflavin binding protein exacerbates degeneration in a model of cone-rod dystrophy, IOVS, 2020. | |
| dc.identifier.uri | https://hdl.handle.net/10657/6700 | |
| dc.language.iso | eng | |
| dc.rights | The author of this work is the copyright owner. UH Libraries and the Texas Digital Library have their permission to store and provide access to this work. UH Libraries has secured permission to reproduce any and all previously published materials contained in the work. Further transmission, reproduction, or presentation of this work is prohibited except with permission of the author(s). | |
| dc.subject | Retbindin | |
| dc.subject | Flavin | |
| dc.subject | Retina | |
| dc.subject | Peripherin2 | |
| dc.subject | Rhodopsin | |
| dc.subject | Mouse model | |
| dc.subject | Retinal degeneration | |
| dc.title | Ablation of Retbindin, the Riboflavin Binding Protein, Exacerbates Retinal Degenerative Phenotypes in Mouse Models of Human Retinal Diseases | |
| dc.type.dcmi | Text | |
| dc.type.genre | Thesis | |
| local.embargo.lift | 2022-05-01 | |
| local.embargo.terms | 2022-05-01 | |
| thesis.degree.college | Cullen College of Engineering | |
| thesis.degree.department | Biomedical Engineering, Department of | |
| thesis.degree.discipline | Biomedical Engineering | |
| thesis.degree.grantor | University of Houston | |
| thesis.degree.level | Doctoral | |
| thesis.degree.name | Doctor of Philosophy |
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