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Studie av synaptologinoch genuttryck i en modell för gnagareefter en lätt traumatisk hjärnskada
KTH, School of Computer Science and Communication (CSC).
2013 (Swedish)Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
Abstract [sv]

Diffusa axonala skador drabbar relativt m°anga personer varje °ar. Dessa skador kan uppst°a vid

kollisionsolyckor i idrottsrelaterade aktiviter, vid fall eller som en bieffekt av pisksn¨artsskador.

Avdelningen f¨or neurovetenskap p°a Karolinska Institutet och avdelnigen f¨or fordonss¨akerhet

p°a Chalmers tekniska h¨ogskola har utvecklat en modell avsedd f¨or gnagare i vilken

f¨oren¨amnda olycksh¨andelser kan simuleras. Detta genom att uts¨atta r°attors huvud f¨or

rotationsaccelerationer. Rotationsaccelerationen kan justeras f¨or att p°a s°a s¨att skapa olika

grader av diffusa axonala skador. Resultatet av en axonal skada beror p°a skadans grad; skador

av h¨ogre grad kan resultera i att drabbade f°ar best°aende men medan en l¨agre grad av skada

kan p°averka olika biologiska mekanismer i cellerna p°a skadade omr°aden. Oberoende av

skadans grad sker det alltid en f¨or¨andring av produktionen av proteiner i p°averkade celler och

deras n¨arliggande celler. Dessa f¨or¨andringar kan uppt¨ackas genom att studera f¨or¨andringar i

genuttrycket i samma celler.

I den h¨ar studien foskuserades fr¨amst p°a att unders¨oka hur tv°a olika grader av

rotationsacceleration p°averkade genuttrycket i r°attor som skadades med hj¨alp av modellen

presenterad ovan. F¨orutom detta unders¨oktes vilka biologiska aktiviteter som kunde ha

p°averkats av skadan. I studien ingick tolv f¨ors¨oksdjur som delades in i fyra grupper best°aende

av tre r°attor var: r°attor som utsattes f¨or en vinkelrotationsacceleration av 1,02

Mrad~s2,

r°attor som utsattes f¨or 1,3

Mrad~s2, r°attor som genomgick samma kirurgiska ingrepp och

blev bed¨ovade p°a samma s¨att som r°attorna i de tv°a f¨orsta grupperna, och en sista grupp av

r°attor som varken genomgick kirurgiskt ingrepp eller skadades. Matriser av typen Affymetrix

GeneChip

® och summeringsalgoritmerna RMA, PLIER och iterPLIER anv¨andes till analysen

av genuttryck. Det genomf¨ordes en genontologisk studie p°a skilt uttryckta gener mellan de

olika grupperna av r°attor. Detta f¨or att unders¨oka vilka biologiska funktioner som kunde ha

p°averkats mest efter skada p°a grund av rotationsaccelerationen och det kirurgiska ingreppet

som djuren hade utsatts f¨or.

Resultatet av analysen av genuttrycket visade att det skedde nedregleringar av mRNAproduktionen

efter kirurgiskt ingrepp och bed¨ovning samt uppreglering av genuttrycket

efter skada orsakad av rotationsacceleration. Det f¨orekom v¨aldigt f°a skillnader i genuttryck

mellan grupperna som hade skadats. De mest p°averkade biologiska funktionerna som kunde

observeras var relaterade till cellul¨ara komponenter i membrana delar av cellen och den

biologiska processen

neurological system process. Resultatet av analysen av genuttrycket

varierade beroende p°a vilken summeringsalgoritm som hade anv¨ants. Av alla tre algoritmerna

gav iterPLIER flest skilt uttryckta gener.

N°agra begr¨ansningar i studien var det l°aga antalet individer som analyserades, att bara djur

av manligt k¨on studerades och avsaknad av dokumentation p°a hur besl¨aktade djuren var. Dessa

begr¨ansningar g¨or resultatet av studien och de slutsatser som kunde dras t¨amligen otillf¨orlitliga.

Abstract [en]

Diffuse axonal injuries are an increasing problem in our ever growing population. Diffuse

axonal injuries can emerge after collision accidents in sports activities where athletes collide

with each other, after falling or hitting the head into objects or after whiplash injuries in

motor vehicle accidents. The department of Neuroscience at Karolinska Institutet and the

division of Vehicle Safety at Chalmers Technical University has developed a rodent model

that mimics such scenarios with the help of a rotational acceleration of rats’ head. The

model can be adjusted to create different levels of rotational acceleration which in turn will

induce different severities of axonal injuries. The outcome of an axonal injury depends on

its severity; high severity injuries can end with long lasting deficiencies while a low severity

injury might affect different biological mechanisms in the cells of affected regions in the

brain. In either case the injury will cause changes in the protein production of affected cells

and neighboring cells. These changes can be traced by studying the changes in gene expression.

The main purpose of the study presented below was to investigate in which manner two

different levels of rotational acceleration (using the rodent model presented above) affected

the gene expression in the brains of rats; taking also into consideration biological changes

that might arise in the cells of affected regions. Twelve rats were divided into four groups

consisting of three individuals each: rats subjected to an angular rotational acceleration of 1.02

Mrad

~s2, rats exposed to 1.3 Mrad~s2, rats that only were operated and anesthetized as the

first two groups and a last group that was not operated. Affymetrix GeneChip

® arrays and

the summarization algorithms RMA, PLIER and iterPLIER were used to the analysis of gene

expression. A gene ontological study of differentially expressed genes between the experiment

groups was performed to get better understanding of which biological functions were affected

the most after exposure to rotational acceleration and operation of the animals.

The gene expression analysis indicated that there was down-regulation of mRNA-production

after surgery and anaesthetization, and up-regulation after rotational acceleration. Very little

differences in regulation of mRNA-production was observed between the two exposed groups.

The most affected biological functions where related to cellular components in membranal

parts of the cell and the biological process

neurological system process. It was also noted that

the results of the analysis varied depending on which summarization algorithm that was used.

Of the three algorithms itePLIER gave more significantly differentially expressed genes.

It is worth noticing that this study was based on groups of very few animals; also all of the same

sex and there existed no heritage documentation on them. These limitations make the results

and all conclusions drawn from them unreliable.

Place, publisher, year, edition, pages
2013.
Series
TRITA-CSC-E, ISSN 1653-5715 ; 13:114
National Category
Computer Science
Identifiers
URN: urn:nbn:se:kth:diva-138027OAI: oai:DiVA.org:kth-138027DiVA: diva2:680245
Educational program
Master of Science in Engineering - Computer Science and Technology
Supervisors
Examiners
Available from: 2013-12-17 Created: 2013-12-17 Last updated: 2015-09-24Bibliographically approved

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