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Characterization of macular disease ...

Farjo, Rafal A.

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Characterization of macular disease models and development of new treatment options.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Characterization of macular disease models and development of new treatment options./
Author:	Farjo, Rafal A.
Description:	176 p.
Notes:	Adviser: Muna I. Naash.
Contained By:	Dissertation Abstracts International67-12B.
Subject:	Biology, Cell. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3244555

Characterization of macular disease models and development of new treatment options.
Farjo, Rafal A.

Characterization of macular disease models and development of new treatment options. - 176 p.

Adviser: Muna I. Naash.

Thesis (Ph.D.)--The University of Oklahoma Health Sciences Center, 2006.

Human blinding disorders are often initiated by hereditary mutations that insult rod and/or cone photoreceptors and cause subsequent cellular death. Mutations in Retinal Degeneration Slow (Rds) manifest as different forms of retinal disease affecting rods, cones, or both photoreceptors; however the precise role of Rds in these two cell types has yet to be elucidated. Herein we demonstrate a differential requirement of Rds during rod and cone outer segment morphogenesis. In the absence of this photoreceptor-specific protein, rods do not form outer segments, and enter apoptosis, whereas cone photoreceptors develop atypical outer segments and are viable. Such outer segments consist of dysmorphic membranous structures devoid of lamellae. These structures fail to associate with the specialized extracellular matrix that surrounds cones, suggesting that Rds per se or normal outer segment formation is required for this interaction. Using microarray analyses, we identified which genes may be responsible for supporting such an abnormal OS structure. In the presence of one functional Rds allele, normal cone OS morphogeneis is attempted, but produces oversized and disorganized lamellae similarly to what occurs in rod photoreceptors. Interestingly, the presence of Rds has a significant impact on the stability of S-opsin protein and causes an upregulation of other cone phototransduction mRNAs, indicative of intracellular signaling between the outer segment and nucleus. These observations also have implications regarding therapeutic strategies as it is possible that a complete absence of Rds may be more advantageous than having mutant isoforms of Rds in cone photoreceptors. Towards this goal, we evaluated the efficiency of compacted DNA nanoparticles as a system for non-viral gene transfer to ocular tissues. Almost all cell types of the eye were capable of nanofection and produced robust levels of gene expression that were dose-dependent. Most impressively, subretinal delivery of these nanoparticles transfected nearly all of the photoreceptor population and produced expression levels almost equal to that of rhodopsin. As no deleterious effects on retinal function were observed, this treatment strategy appears to provide a safe an efficient method to safely deliver and express nucleic acids in ocular tissues.Subjects--Topical Terms:

1017686
Biology, Cell.

Characterization of macular disease models and development of new treatment options.
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100 1 $a Farjo, Rafal A. $3 1269279
245 1 0 $a Characterization of macular disease models and development of new treatment options.
300 $a 176 p.
500 $a Adviser: Muna I. Naash.
500 $a Source: Dissertation Abstracts International, Volume: 67-12, Section: B, page: 7019.
502 $a Thesis (Ph.D.)--The University of Oklahoma Health Sciences Center, 2006.
520 $a Human blinding disorders are often initiated by hereditary mutations that insult rod and/or cone photoreceptors and cause subsequent cellular death. Mutations in Retinal Degeneration Slow (Rds) manifest as different forms of retinal disease affecting rods, cones, or both photoreceptors; however the precise role of Rds in these two cell types has yet to be elucidated. Herein we demonstrate a differential requirement of Rds during rod and cone outer segment morphogenesis. In the absence of this photoreceptor-specific protein, rods do not form outer segments, and enter apoptosis, whereas cone photoreceptors develop atypical outer segments and are viable. Such outer segments consist of dysmorphic membranous structures devoid of lamellae. These structures fail to associate with the specialized extracellular matrix that surrounds cones, suggesting that Rds per se or normal outer segment formation is required for this interaction. Using microarray analyses, we identified which genes may be responsible for supporting such an abnormal OS structure. In the presence of one functional Rds allele, normal cone OS morphogeneis is attempted, but produces oversized and disorganized lamellae similarly to what occurs in rod photoreceptors. Interestingly, the presence of Rds has a significant impact on the stability of S-opsin protein and causes an upregulation of other cone phototransduction mRNAs, indicative of intracellular signaling between the outer segment and nucleus. These observations also have implications regarding therapeutic strategies as it is possible that a complete absence of Rds may be more advantageous than having mutant isoforms of Rds in cone photoreceptors. Towards this goal, we evaluated the efficiency of compacted DNA nanoparticles as a system for non-viral gene transfer to ocular tissues. Almost all cell types of the eye were capable of nanofection and produced robust levels of gene expression that were dose-dependent. Most impressively, subretinal delivery of these nanoparticles transfected nearly all of the photoreceptor population and produced expression levels almost equal to that of rhodopsin. As no deleterious effects on retinal function were observed, this treatment strategy appears to provide a safe an efficient method to safely deliver and express nucleic acids in ocular tissues.
590 $a School code: 0361.
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650 4 $a Biology, Molecular. $3 1017719
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