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Studies into The Mechanisms of Neurodegeneration and Neuroprotection in Rd1 Mouse Retina.

Azadi, Seifollah LU (2006) In Lund University Faculty of Medicine Doctoral Dissertation Series 2006:17.
Abstract
Retinitis Pigmentosa (RP) is a group of uncured retinal diseases with the world wide incidence of about 1/3500. In spite of the huge efforts in past years, the mechanisms underlying this type of hereditary blindness has not been elucidated and nor any effective treatment available.



The rd1 mouse strain carries a mutation in ?-subunit of phosphodiesterase gene which hydrolyzes the cGMP and is needed for normal visual phototransduction. Once this enzyme is impaired, the cGMP gated channels remain in the open state. This raise the intracellular Ca2+ beyond physiological level and this is believed to be the main cause for photoreceptor cell death in rd1 mouse retina. Since this mutation is homologous to some form of human... (More)
Retinitis Pigmentosa (RP) is a group of uncured retinal diseases with the world wide incidence of about 1/3500. In spite of the huge efforts in past years, the mechanisms underlying this type of hereditary blindness has not been elucidated and nor any effective treatment available.



The rd1 mouse strain carries a mutation in ?-subunit of phosphodiesterase gene which hydrolyzes the cGMP and is needed for normal visual phototransduction. Once this enzyme is impaired, the cGMP gated channels remain in the open state. This raise the intracellular Ca2+ beyond physiological level and this is believed to be the main cause for photoreceptor cell death in rd1 mouse retina. Since this mutation is homologous to some form of human blindness, the rd1 mouse retina is considered as an ideal model for studying retina degeneration in human.



The genes which are differentially expressed at a crucial time point of the degenerative process in the rd1 mouse retina could increase our current understanding of pathways involved in photoreceptor cell demise. We applied a microarray analysis to perform a global screening of rd1 mouse retina and the age matched wild type counterparts at post natal day 11. At this age the decision for the death of rd1 photoreceptors has been made but cells are mostly not yet eliminated.



In the first part of the study (microarray analysis) we identified 328 up regulated and 110 downregulated genes. Gene ontology analysis was used to categorize these genes. Further studies showed that calpain activity is much higher in rd1 photoreceptor and might be involved in photoreceptor cell death. Our data also showed that mRNA and protein level of three members of novel PKCs ?, ? and µ were increased in rd1. Moreover, PKC ?, ? are more phosphorylated in rd1 retina. The changes are partly located in photoreceptor layer and therefore they could very well be related to the rd1 induced cell death.



In this work we also aimed at understanding the molecular events which take place following application of a combination of neurotrophic factors namely CNTF+ BDNF in rd1 retina explants. Following the above mentioned treatment, endogenous BDNF, CNTF, GFAP, p-ERK, p-Akt levels were increased and FGF2 level was decreased. Rd1 treated explants compared to untreated counterparts showed less tunnel positive cells. The observed changes suggest that CNTF+BDNF stimulates survival signaling pathways which might creates a prospective treatment for RP patients. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Professor of Medical Genetics and Ophthalmology Aguirre, Gustavo, Section of Medical geneticsSchool of Veterinary Medicine, University of Pennsylvania
organization
publishing date
type
Thesis
publication status
published
subject
keywords
'signaling pathway', Ophtalmology, 'neurotrophic factors', Oftalmologi, 'retina degeneration'
in
Lund University Faculty of Medicine Doctoral Dissertation Series
volume
2006:17
pages
70 pages
publisher
Ophthalmology (Lund), Lund University
defense location
GK salon, BMC
defense date
2006-02-24 13:15:00
ISSN
1652-8220
ISBN
91-85481-43-2
language
English
LU publication?
yes
additional info
id
01004e69-2a48-4bd9-85dc-c681991279a1 (old id 546270)
date added to LUP
2016-04-01 15:39:01
date last changed
2019-05-21 22:14:48
@phdthesis{01004e69-2a48-4bd9-85dc-c681991279a1,
  abstract     = {Retinitis Pigmentosa (RP) is a group of uncured retinal diseases with the world wide incidence of about 1/3500. In spite of the huge efforts in past years, the mechanisms underlying this type of hereditary blindness has not been elucidated and nor any effective treatment available.<br/><br>
<br/><br>
The rd1 mouse strain carries a mutation in ?-subunit of phosphodiesterase gene which hydrolyzes the cGMP and is needed for normal visual phototransduction. Once this enzyme is impaired, the cGMP gated channels remain in the open state. This raise the intracellular Ca2+ beyond physiological level and this is believed to be the main cause for photoreceptor cell death in rd1 mouse retina. Since this mutation is homologous to some form of human blindness, the rd1 mouse retina is considered as an ideal model for studying retina degeneration in human.<br/><br>
<br/><br>
The genes which are differentially expressed at a crucial time point of the degenerative process in the rd1 mouse retina could increase our current understanding of pathways involved in photoreceptor cell demise. We applied a microarray analysis to perform a global screening of rd1 mouse retina and the age matched wild type counterparts at post natal day 11. At this age the decision for the death of rd1 photoreceptors has been made but cells are mostly not yet eliminated.<br/><br>
<br/><br>
In the first part of the study (microarray analysis) we identified 328 up regulated and 110 downregulated genes. Gene ontology analysis was used to categorize these genes. Further studies showed that calpain activity is much higher in rd1 photoreceptor and might be involved in photoreceptor cell death. Our data also showed that mRNA and protein level of three members of novel PKCs ?, ? and µ were increased in rd1. Moreover, PKC ?, ? are more phosphorylated in rd1 retina. The changes are partly located in photoreceptor layer and therefore they could very well be related to the rd1 induced cell death.<br/><br>
<br/><br>
In this work we also aimed at understanding the molecular events which take place following application of a combination of neurotrophic factors namely CNTF+ BDNF in rd1 retina explants. Following the above mentioned treatment, endogenous BDNF, CNTF, GFAP, p-ERK, p-Akt levels were increased and FGF2 level was decreased. Rd1 treated explants compared to untreated counterparts showed less tunnel positive cells. The observed changes suggest that CNTF+BDNF stimulates survival signaling pathways which might creates a prospective treatment for RP patients.},
  author       = {Azadi, Seifollah},
  isbn         = {91-85481-43-2},
  issn         = {1652-8220},
  language     = {eng},
  publisher    = {Ophthalmology (Lund), Lund University},
  school       = {Lund University},
  series       = {Lund University Faculty of Medicine Doctoral Dissertation Series},
  title        = {Studies into The Mechanisms of Neurodegeneration and Neuroprotection in Rd1 Mouse Retina.},
  volume       = {2006:17},
  year         = {2006},
}