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Intracellular mechanisms in rd1 mouse retinal degeneration

Johnson, Leif LU (2007) In Lund University Faculty of Medicine Doctoral Dissertation Series
Abstract
Retinitis pigmentosa (RP) is an inherited disorder and the leading cause of visual impairment in the working age population. It is caused by a number of different genetic mutations, all of which cause the rod photoreceptors to degenerate. As the rods become few in numbers, the cones will also begin to die, resulting in total blindness. Since the genetic defects leading to RP are numerous, it would be overwhelming to treat each variation individually. By finding mechanisms related to photoreceptor survival and degeneration which are common to all forms of RP, a more general therapy can be developed.



The rd1 mouse is an animal model of RP used to study these processes. Changes in retinal cells as a result of the rd1... (More)
Retinitis pigmentosa (RP) is an inherited disorder and the leading cause of visual impairment in the working age population. It is caused by a number of different genetic mutations, all of which cause the rod photoreceptors to degenerate. As the rods become few in numbers, the cones will also begin to die, resulting in total blindness. Since the genetic defects leading to RP are numerous, it would be overwhelming to treat each variation individually. By finding mechanisms related to photoreceptor survival and degeneration which are common to all forms of RP, a more general therapy can be developed.



The rd1 mouse is an animal model of RP used to study these processes. Changes in retinal cells as a result of the rd1 mutation are characterized and manipulated using an in vitro system. Paper I describes how the signaling protein Akt is activated in correlation with developmental and pathological cell death and may be part of an endogenous survival program. Paper II investigates the retinal response to the CNTF and BDNF and shows how their own regulation is increased and the signaling proteins Akt, ERK and CREB are activated. Paper III illustrates the protective effects of antioxidant treatment on rd1 photoreceptors. Paper IV investigates the activation of JNK and c-Jun and evaluates their roles in rd1 degeneration. Paper V simulates the rd1 mutation pharmacologically at different ages and shows how intracellular mechanisms are affected by photoreceptor development. Characterizations such as these will help in the development of therapeutic strategies for RP. (Less)
Abstract (Swedish)
Popular Abstract in Swedish

Ärftlig blindhet orsakas oftast av sjukdomar där näthinnans fotoreceptorer, som ombesörjer omvandlingen av ljus till elektriska impulser, degenererar. Det anses att denna celldödsprocess styrs av ett antal olika mekanismer och projektets mål är att försöka identifiera och karaktärisera dessa mekanismer. Retinitis Pigmentosa (RP) är en ärftlig sjukdom där en genetisk defekt orsakar celldöd hos fotoreceptorer. Arbetet använder sig av en RP djur modell, rd1-möss, som har en genetisk mutation vilket leder till en både tidig och snabb degeneration av fotoreceptorerna. Uttrycket och förändringar hos olika proteiner, mRNA och DNA i rd1-mössen jämfördes med det i normala möss med hjälp av metoder som... (More)
Popular Abstract in Swedish

Ärftlig blindhet orsakas oftast av sjukdomar där näthinnans fotoreceptorer, som ombesörjer omvandlingen av ljus till elektriska impulser, degenererar. Det anses att denna celldödsprocess styrs av ett antal olika mekanismer och projektets mål är att försöka identifiera och karaktärisera dessa mekanismer. Retinitis Pigmentosa (RP) är en ärftlig sjukdom där en genetisk defekt orsakar celldöd hos fotoreceptorer. Arbetet använder sig av en RP djur modell, rd1-möss, som har en genetisk mutation vilket leder till en både tidig och snabb degeneration av fotoreceptorerna. Uttrycket och förändringar hos olika proteiner, mRNA och DNA i rd1-mössen jämfördes med det i normala möss med hjälp av metoder som immunoblot, RT-PCR, Northern blot samt immunfärgning av snittad vävnad. Dessutom, för att experimentellt påverka de intracellulära mekanismerna i fotoreceptorerna odlades i en del av undersökningarna näthinnor i ett in vitro system, där olika substanser tillsattes så att deras effekter i efterhand kunde studeras. Denna metod användes även med näthinnor från normala möss, som behandlades med en substans som orsakar degeneration på ett sätt som liknar rd1-mössens patologi. I sammanfattning visar arbetena att genom att undersöka de mekanismer som jobbar antingen för eller emot celldöd hos fotoreceptorerna i en degenerationsmodell, och hur dessa mekanismer kan påverkas, är det möjligt att befrämja de drabbade cellernas överlevnad. Informationen som dessa experimentella studier gett upphov till kan därför hjälpa till att förbättra utvecklingen och värderingen av behandlingar för sjukdomar som RP. (Less)
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author
supervisor
opponent
  • Professor Karlsson, Jan-Olof, Göteborg University
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Ophtalmology, Neuroprotection, Photoreceptor, Retinitis Pigmentosa, Oftalmologi
in
Lund University Faculty of Medicine Doctoral Dissertation Series
pages
130 pages
publisher
Faculty of Medicine, Lund University
defense location
Segerfalksalen BMC Hus A Sölvegatan 19 Lund
defense date
2007-09-28 13:00:00
ISSN
1652-8220
ISBN
978-91-85897-07-0
language
English
LU publication?
yes
additional info
Leif E Johnson, Theo van Veen and Per A Ekstrom. 2005. Differential Akt activation in the photoreceptors of normal and rd1 mice. Cell Tissue Res., vol 320 pp 213-22.
Seifollah Azadi, Leif E Johnson, Francois Paquet-Durand, Maithé T Perez, Yiqin Zhang, Per A Ekstrom and Theo van Veen. 2007. CNTF+BDNF treatment and neuroprotective pathways in the rd1 mouse retina. Brain Res, vol 1129 pp 116-29.
Maria M Sanz, Leif E Johnson, Satpal Ahuja, Per A Ekstrom, Javier Romero and Theo van Veen. 2007. Significant photoreceptor rescue by treatment with a combination of antioxidants in an animal model for retinal degeneration. Neuroscience, vol 145 pp 1120-9.
Leif E Johnson, Sandra Dahl, Theo van Veen and Per AR Ekström. 2007. cJun signaling in degenerating photoreceptors of rd1 mice. (submitted)
Leif E Johnson and Per AR Ekström. 2007. Developmental stage affects photoreceptor response in an induced model of retinitis pigmentosa. (manuscript)
id
d2ab4af8-b608-4f63-aa0a-090aef64f7b4 (old id 598886)
date added to LUP
2016-04-01 15:47:59
date last changed
2019-05-22 05:56:57
@phdthesis{d2ab4af8-b608-4f63-aa0a-090aef64f7b4,
  abstract     = {{Retinitis pigmentosa (RP) is an inherited disorder and the leading cause of visual impairment in the working age population. It is caused by a number of different genetic mutations, all of which cause the rod photoreceptors to degenerate. As the rods become few in numbers, the cones will also begin to die, resulting in total blindness. Since the genetic defects leading to RP are numerous, it would be overwhelming to treat each variation individually. By finding mechanisms related to photoreceptor survival and degeneration which are common to all forms of RP, a more general therapy can be developed.<br/><br>
<br/><br>
The rd1 mouse is an animal model of RP used to study these processes. Changes in retinal cells as a result of the rd1 mutation are characterized and manipulated using an in vitro system. Paper I describes how the signaling protein Akt is activated in correlation with developmental and pathological cell death and may be part of an endogenous survival program. Paper II investigates the retinal response to the CNTF and BDNF and shows how their own regulation is increased and the signaling proteins Akt, ERK and CREB are activated. Paper III illustrates the protective effects of antioxidant treatment on rd1 photoreceptors. Paper IV investigates the activation of JNK and c-Jun and evaluates their roles in rd1 degeneration. Paper V simulates the rd1 mutation pharmacologically at different ages and shows how intracellular mechanisms are affected by photoreceptor development. Characterizations such as these will help in the development of therapeutic strategies for RP.}},
  author       = {{Johnson, Leif}},
  isbn         = {{978-91-85897-07-0}},
  issn         = {{1652-8220}},
  keywords     = {{Ophtalmology; Neuroprotection; Photoreceptor; Retinitis Pigmentosa; Oftalmologi}},
  language     = {{eng}},
  publisher    = {{Faculty of Medicine, Lund University}},
  school       = {{Lund University}},
  series       = {{Lund University Faculty of Medicine Doctoral Dissertation Series}},
  title        = {{Intracellular mechanisms in rd1 mouse retinal degeneration}},
  year         = {{2007}},
}