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Uloga kongeničnih štakora BN.GH u pozicijskom kloniranju gena ključnih u patogenezi hipertenzije : doktorska disertacija

Fakulteti, doktorske disertacije Vrsta gradje
Naslov
Uloga kongeničnih štakora BN.GH u pozicijskom kloniranju gena ključnih u patogenezi hipertenzije : doktorska disertacija / Marijo Bilušić ; [voditelj rada Mladen Boban]. -
Impresum
Split : M. Bilušić, 2005. ([s. l. : s. n.]). -
Materijalni opis
VII, 103 lista : graf. prikazi u bojama ; 30 cm. -
Uputnica
Jezik
hrv, eng
Napomena
Na vrhu nasl. str.: Sveučilište u Splitu, Medicinski fakultet.
Bibliografija: listovi 88-101. Summary: The role of BN.GH congenic rat strains in genetic dissection of hypertension.

SUMMARY

The role of BN.GH congenic rat strains in genetic dissection of hypertension .
This dissertation represents an attempt to dissect the genetic etiology of hypertension using a genetically modified experimental model: BN.GH congenic rats.
All described experiments were a constitutive part of the NHLBI Family Blood Pressure Program.
The objective was to positionally clone hypertension gene(s) and to accelerate genetic studies in humans using a GH model.
The aims of this study were to determine how selected regions of the GH genome on the healthy genomic background, affect blood pressure regulation, blood biochemistry, thyroid hormone levels and vasoactive responses to challenge with LNAME,
NA and ANG II.
We mapped three quantitative trait loci (QTL) contributing to hypertension on chromosomes 2, 6 and 18, using an F2 intercross between the GH/Omr (GH) and normotensive BN/Elh (BN) strains.
Congenic strains for each of the three hypertension loci were generated, introgressing each QTL from the hypertensive GH
onto the normotensive BN background as follows: BN.GH-(D2Rat22-D2Mgh11)/Mcwi (BN.GH2); BN.GH-(D6Mit12-D6Rat15)/Mcwi (BN.GH6) and BN.GH-(D18Rat41D18Mgh4)/Mcwi (BN.GH18).
None of the congenics showed a significant increase in basal blood pressure; given the likelihood that hypertension results from variation in a number of pathways, we investigated the possibility that underlying intermediate phenotypes were dysfunctional but did not independently lead to increased blood pressure.
Consequently, the effects of pharmacological challenges on blood pressure regulation, biometric measurements and blood biochemistry were studied. With this approach we tried to speed up the gene discovery process by dissecting the main, complex phenotype (in this case hypertension) into prohypertensive sub-phenotypes, which are under the control of a limited number of genes.
Our findings suggest that BN.GH2 and BN.GH18 congenic rats do have significantly different blood pressure sub-phenotypes (phenotypes hypothesized to be intermediate phenotypes) and decreased baroreceptor sensitivity (only BN.GH18) compared to BN.
These phenotypes are strongly genetically determined since single QTL introgression significantly changed vasoreactivity and baroreflex sensitivity.
These data suggest that the development of hypertension in GH rats is not under the control of a single “main” gene and that is necessary to have more than one dysfunctional part of the genome to initiate onset of hypertension.
Furthermore, hypertension in this model is probably induced by an epistatic effect of more than one part of the genome, which when combined, may exceed a threshold effect leading to hypertension.
One possible approach to determine a threshold or background effect would be to construct double or triple congenic animals by crossing all existing congenic BN.GH lines.
This may permit the elucidation of gene – gene interactions and the regulation of causative and/or compensatory pathways.

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