Spelling suggestions: "subject:"mammalian target off rapamycin (mTOR)"" "subject:"mammalian target off apamycin (mTOR)""
1 |
The Role of Hypoxia on Pyruvate Kinase M2, mammalian Target of Rapamycin, Mitochondrial Function, and Cell Invasion in the TrophoblastKimball, Rebecca Lutz 01 March 2016 (has links) (PDF)
This thesis will be organized into two chapters discussing the role of hypoxia in the human placenta. The goal of this thesis is to characterize pyruvate kinase M2, mammalian target of rapamycin, mitochondrial function, and cell invasion in hypoxic conditions in the trophoblast. Understanding the mechanisms of placental metabolism can lead to further treatments for placental diseases. Chapter one covers the background of intrauterine growth restriction, hypoxia, placental metabolism, and pyruvate kinase M2 (PKM2). Little is currently understood about the role of the mitochondria in placental diseases. Expression of PKM2, trophoblast cell invasion, and mitochondrial function is shown to be inhibited by hypoxia. PKM2 inhibition decreases trophoblast cell invasion and nuclear expression of PKM2, but increases mitochondrial function. Studying how hypoxia affects the placenta during placental diseases can help clarify the mechanisms by which these diseases occur. Chapter two further characterizes the background of intrauterine growth restriction and hypoxia. It also covers the background of mammalian target of rapamycin. The objective of this chapter was to assess activated mTOR in the trophoblast in hypoxia. Decreased placental and fetal weights, as well as trophoblast cell invasion were observed in hypoxia. A decrease in the activation of mTOR was also found in the hypoxic placenta. This study could provide insight into the physiological relevance of the pathways and could be targeted to help alleviate placental diseases.
|
2 |
Modification of ion channel auxiliary subunits in cardiac diseaseAl Katat, Aya 10 1900 (has links)
L’infarctus du myocarde (IM) survenant après l’obstruction de l’artère coronaire est la cause
principale des décès cardiovasculaires. Après l’IM, le coeur endommagé répond à l’augmentation
du stress hémodynamique avec une cicatrice et une hypertrophie dans la région non-infarcie du
myocarde. Dans la région infarcie, la cicatrice se forme grâce au dépôt du collagène. Pendant
formation de la cicatrice, les cardiomyocytes ventriculaires résidant dans la région non-infarcie
subissent une réponse hypertrophique après l’activation chronique due au système sympathique et
à l’angiotensine II. La cicatrisation préserve l’intégrité structurale du coeur et l'hypertrophie des
cardiomyocytes apporte un support ionotropique.
Le canal CaV1.2 joue un rôle dans la réponse hypertrophique après l’IM. L’activation du
CaV1.2 déclenche la signalisation dépendante de Ca2+ induisant l’hypertrophie. Cependant, il est
rapporté que l’ouverture des canaux potassiques (KATP) ATP sensitifs joue un rôle sélectif dans
l’expansion de la cicatrice après IM. Malgré leur expression dans les coeurs mâles, les KATP
fournissent une cardioprotection sexe dépendante limitant l’expansion de la cicatrice chez les
femelles.
L’administration de rapamycine aux rates ayant subi un infarctus produit l’expansion de la
cicatrice, soutenant la relation possible entre la cible de rapamycine, mTORC1 et les KATP dans la
cardioprotection sexe spécifique.
Effectivement, dans les cellules pancréatiques α, la signalisation mTORC1 était couplée à
l'activation du KATP. Cependant, le lien entre mTORC1 et les canaux KATP dans le coeur reste
inconnu. L'objectif de la thèse est d’examiner le rôle des canaux ioniques dans le remodelage
cardiaque post-IM, surtout des canaux calciques dans l'hypertrophie et d'élucider la relation entre
les KATP et mTORC1.
L’hypothèse première teste que l’hypertrophie médiée par le système sympathique des
cardiomyocytes ventriculaires des rats néonataux (NRCM) produit une augmentation de l’influx
calcique après une augmentation des sous-unités du CaV1.2. Le traitement de norépinéphrine (NE)
quadruple l’amplitude du courant calcique type L et double l’expression protéique des sous unités
de CaVα2δ1 et CaVβ3. L’hypertrophie des NRCM au NE s’associe à une augmentation de la
phosphorylation de la Kinase ERK 1/2. Le β1-bloqueur metoprolol et l’inhibiteur
ii
de ERK1/2 diminuent l’effet de NE sur CaVα2δ1. Cependant, l’augmentation de CaVβ3 et de la
réponse hypertrophique persiste. Ainsi, le signal β1-adrenergique à travers ERK augmente les
sous-unités CaVα2δ1 outre l’hypertrophie.
L’autre hypothèse examine la spécificité du sexe sur l’expansion cicatricielle médiée par
rapamycine et l’influence de mTOR sur l’expression de KATP. Rapamycin augmente la surface de
la cicatrice et inhibe la phosphorylation de mTOR chez les coeurs de femelles. Dans les coeurs des
deux sexes, la phosphorylation de mTOR et l’expression de KATP, Kir6.2 et SUR2A sont
similaires. Cependant, une grande inactivation de la tubérine et une faible expression de raptor
sont détectées chez les femelles. Le traitement à l’ester de phorbol des NRCM induit
l’hypertrophie, augmente la phosphorylation de p70S6K et l’expression SUR2A. Le prétraitement
par Rapamycine atténue chacune des réponses. Rapamycin démontre un patron d’expansion
cicatriciel sexe spécifique et une régulation de phosphorylation de mTOR dans IM. Aussi,
l’augmentation de SUR2A dans les NRCM traités par PDBu révèle une interaction entre mTOR
et KATP. / Myocardial infarction (MI) secondary to the obstruction of the coronary artery is the main cause
of cardiovascular death. Following MI, the damaged heart adapts to the increased hemodynamic
stress via formation of a scar and a hypertrophic response of ventricular cardiomyocytes in the
non-infarcted myocardium. In the infarcted region, a scar is formed via the rapid deposition of
collagen. With ongoing scar formation, ventricular cardiomyocytes in the non-infarcted
myocardium undergo a hypertrophic response secondary to the chronic activation by the
sympathetic system and angiotensin II. Collectively, scar formation and cardiomyocyte
hypertrophy preserve the structural integrity of the heart and provide inotropic support,
respectively.
CaV1.2 channels play a significant role in the hypertrophic response post-MI. Notably, the
activation of CaV1.2 channel triggers Ca2+-dependent signaling that induces hypertrophy. By
contrast, the opening of ATP-sensitive potassium (KATP) channels was shown to partake in
selective scar expansion following MI. Notwithstanding its expression in male hearts, KATP
channels endow a sex-dependent cardioprotection limiting scar expansion selectively in females.
Moreover, administration of the macrolide rapamycin to the infarcted female rat heart led to scar
expansion, supporting the possible relationship between the target of rapamycin, mTORC1 and
KATP channels in providing sex-specific cardioprotection. Indeed, in pancreatic-α cells, mTORC1
signaling was coupled to KATP channel activation. However, whether mTORC1 targets KATP
channels in the heart remains unknown. Thus, the AIM of the thesis was to explore the role of ion
channels in cardiac remodeling post-MI by specifically addressing the role of Ca channels in
cardiomyocyte hypertrophy and elucidate the potential relationship between KATP channels and
mTORC1 signaling.
The first study tested the hypothesis that hypertrophied neonatal rat ventricular
cardiomyocytes (NRVMs) following sympathetic stimulation translated to an increase in calcium
influx secondary to the augmentation of CaV1.2 channel subunits. NE treatment led to a 4-fold
increase of L-type Ca2+ peak current associated with a 2-fold upregulation of CaVα2δ1 and CaVβ3
protein subunits in hypertrophied NRVMs. The hypertrophic response of NNVMs to NE was
associated with the increased phosphorylation of extracellular regulated kinase (ERK1/2). The β1-blocker metoprolol and the ERK1/2 inhibitor suppressed NE-mediated protein upregulation of
CaVα2δ1 whereas CaVβ3 upregulation and the hypertrophic response persisted. Therefore,
sympathetic mediated β1-adrenergic signaling via ERK selectively upregulated the CaVα2δ1
subunit independent of NRVM hypertrophy.
The second study tested the hypothesis that rapamycin-mediated scar expansion was sexspecific and mTOR influenced KATP channel subunit expression. Rapamycin administration
translated to scar expansion and inhibited mTOR phosphorylation exclusively in females. In
normal adult male and female rat hearts, mTOR phosphorylation and protein levels of KATP
channel subunits Kir6.2 and SUR2A were similar. However, greater tuberin inactivation and
reduced raptor protein levels were detected in females. NRVMs treated with a phorbol ester
induced hypertrophy, increased p70S6K phosphorylation and SUR2A protein levels and
rapamycin pretreatment attenuated each response. Thus, rapamycin administration to MI rats
unmasked a sex-specific pattern of scar expansion and highlighted the disparate regulation of
mTOR phosphorylation. Moreover, rapamycin-dependent upregulation of SUR2A in PDButreated NRVMs revealed a novel interaction between mTOR and KATP channel subunit expression
|
Page generated in 0.0602 seconds