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|Title:||Investigating the Role of the JAK/STAT Pathway and DNA Damage Response (DDR) Pathways in Testicular Ischemia Reperfusion Injury||Authors:||Farah Ahmed Khashab||Supervisor:||Dr. May Al-Maghrebi||Degree Awarded:||M.Sc. Degree in: Medical Biochemistry||Keywords:||DDR pathways ; Germ Cell Apoptosis ; JAK/STAT pathway ; DNA Damage ; Testicular Ischemia Reperfusion Injury||Issue Date:||2019||Publisher:||Kuwait university - college of graduate studies||Abstract:||Testicular torsion and detorsion is a urological emergency caused by the obstruction and re-flow of blood due to the twisting and untwisting of the spermatic cord explained as a testicular ischemia reperfusion injury (tIRI). Such pathological event causes oxidative stress-induced DNA damage leading to germ cell apoptosis (GCA). The aim is to investigate the internal mechanism linking the JAK/STAT signaling pathway with the DNA damage response (DDR) signaling pathways and their effect on tIRI-induced oxidative DNA damages. Male Sprague-Dawley rats (n=36) were divided into 3 groups: sham, unilateral tIRI and tIRI+AG490 (40 mg/kg), a JAK inhibitor. The tIRI was induced by the obstruction of the spermatic cord using a surgical clamp. Spermatogenesis was evaluated using histological analysis. Apurinic/apyrimidinic sites (AP) and 8-OHdG formation were estimated using DNA damage quantification kits. Expression of the JAK/STAT pathway was assessed using immunohistochemistry and the activation of the DDR signaling pathways was detected by Western blot. Spermatogenesis arrest was indicated by the presence of spermatocytes but few early spermatids were clear during tIRI. There was also a significant increase in the tIRI-induced oxidative DNA damage in the form of DNA strand breaks and AP sites and 8-OHdG formation. Moreover, tIRI-induced DNA damage caused significant rise in the phosphorylation levels of the JAK2/STAT1/STAT3 proteins. Both DDR signaling pathways: ATM/CHEK2 and ATR/ CHEK1 were activated as judged by the significant overexpression of their phosphorylated forms. The tIRI-induced GCA and DNA damage was blocked by inhibition of JAK activity. Our findings suggest that tIRI-induced DNA damage and GCA was prompted by activation of the JAK/STAT signaling pathway, which directed the apoptosis decision by the activation of the ATM/CHEK2 and ATR/CHEK1 DDR signaling pathways.||URI:||http://hdl.handle.net/123456789/1002|
|Appears in Programs:||0540 Medical Biochemistry (M.Sc.)|
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