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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
31

Μοριακοί μηχανισμοί ελέγχου της μετάδοσης του σήματος της αυξητικής ορμόνης σε παιδιά με σοβαρή ανεπάρκεια στην αύξηση

Καραγεώργου, Ιουλία 22 March 2011 (has links)
Περιγράψαμε την Διαταραχή Μεταγωγής Σήματος Αυξητικής Ορμόνης (GHTD), σε παιδιά με σοβαρή καθυστέρηση ανάπτυξης, φυσιολογική έκκριση αυξητικής ορμόνης (GH), χαμηλό IGF-I αλλά φυσιολογική ανταπόκριση IGF-I σε χορήγηση hGH, που παρουσιάζουν ελαττωματική φωσφορυλίωση του STAT3. Η διαταραχή θεραπεύεται με hGH. Οι CIS πρωτεΐνες είναι αρνητικοί ρυθμιστές του σηματοδοτικου μονοπατιού της GH που ανταγωνίζονται STATs για θέση πρόσδεσης με τον υποδοχέα GHR ή συμμετέχουν στην αποδόμηση του JAK2/GHR μέσω ουβυκουιτίνης/προτεασώματος. Η αδυναμία φωσφορυλίωσης του STAT3 και JAK2 φαινεται να προσπερνάται με χρήση εναλακτικής οδου. Με ‘διασυνομιλία’ της GH με το μονοπάτι του EGF. Συγκεκριμένα η GH φωσφωρυλιώνει το EGFR μέσω φωσφορυλίωσης JAK2. Τέλος, η φωσφορυλίωση STAT3 προκαλείται και από την 17β-οιστραδιόλη. Υπάρχει μία κλινική οντότητα της “καθυστέρησης της ήβης και ανάπτυξης” όπου γίνεται σημαντική επιτάχυνση στην ανάπτυξη μετά την εφηβεία όπου υπάρχει φυσιολογικό τελικό ανάστημα που ταιριάζει με την πορεία ενός ασθενή. Σκοπός: Μελετήθηκε η αρνητική ρύθμιση της GH σε ινοβλάστες παιδιών με GHTD και φυσιολογικών. Στη συνέχεια, η πιθανή συσχέτιση του σηματοδοτικού μονοπατιού της GH και EGF στα παιδιά και τέλος η πιθανή συσχέτιση των στερεοειδών του φύλου με το GH άξονα σε ένα GHTDπαιδί . Yλικά/μέθοδοι: Σε πρωτογενείς καλλιέργειες ινοβλαστών ούλων μαρτύρων και GHTD παιδιών μελετήσαμε την έκφραση και ενεργοποίηση της CIS και JAK2, με επαγωγή με hGH, με Western blot. Στη συνέχεια μελετήθηκε η έκφραση του EGF και pEGF στα κύτταρα των παιδιών και μαρτύρων με επαγωγή των κυττάρων με GH και EGF έλεγχος με Western blot και coimmunoprecipitation. Τέλος μελετήθηκε η φωσφoρυλίωση STAT3 και JAK2 σε ινοβλαστες (προεφηβικούς και εφηβικούς) του ασθενή με GH και 17-β οιστραδιόλη με Western immunoblotting. Αποτελέσματα: Η έκφραση του CIS με 200 ng/ml hGH έδειξε μόνο στους ασθενείς αύξηση της συνολικής CIS και της ουβικουτινυλιομενής μορφής της. Η έκφραση και ενεργοποίηση τoυ JAK2 μόνο στους ασθενείς με επαγωγή με hGΗ δείχνει καθυστερημένη ενεργοποίηση του. Το STAT3 φωσφωρυλιώνεται φυσιολογικά με επαγωγή των κυττάρων των ασθενών με EGF όχι με GH. Οι pEGFRs φωσφωρυλιώνουν φυσιολογικά το JAK2 στους ασθενείς, ενώ όχι στους μάρτυρες. Ο ένας ασθενής προεφηβικά δε φωσφωρυλιώνει το STΑT3 με GH. Εμφανίζει την ουβικουτινιλιωμένη μορφή του CIS. Δεν φωσφωρυλιώνει το STAT3 με 17β-οιστραδιόλη προ-εφηβικά, και εμφανίζει την ουβικουτινιλιωμένη μορφή του CIS. Ενώ εφηβικά φωσφορυλιώνει το STAT3 με 17β-οιστραδιόλη και δεν εμφανίζει την ουβικουτινιλιωμένη μορφή του CIS. Συμπεράσματα: Βρέθηκε καθυστερημένη ενεργοποίηση του GH άξονα σε 2 ασθενής με GHTD μαζί με υπερέκφραση της CIS και ουβικουτινυλιομενής CIS. Η σηματοδότηση της GH γίνεται φυσιολογικά στους μάρτυρες άρα δεν υπάρχει λόγος εναλλακτικής οδού, σε αντίθεση με ασθενείς που χρειάζεται να χρησιμοποιήσουν το μονοπάτι του EGF. Ο ένας ασθενής ξεπέρασε την αδυναμία να φωσφορυλιώσει το STAT3 χωρίς hGH αλλά με την έναρξη της εφηβείας. Ένας λόγος που το παιδί αυτό έδειξε σημαντική επιτάχυνση στην ανάπτυξη είναι ότι μετά την εφηβεία δεν υπήρχε υπερλειτουργία του ανασταλτικού μηχανισμού της GH, διαμέσου του Ub CIS. / We have previously described a new disorder (GHTD) in 4 children with growth delay, normal provoked and spontaneous GH secretion, and low IGF-I concentrations but normal IGF-I generation test results who have a defect in the phosphorylation of the signal transducer and activator of transcription STAT-3. These children respond with a significant increase in their growth velocity after administration of hGH. CIS proteins are inhibitors of the GH signal transduction pathway, by distinct mechanisms: by competition with STATs for common tyrosine-binding sites on the cytoplasmic tail of GHR or by a proteasome-dependent mechanism. Monoubiquitinated form of CIS protein was observed in 2 GHTD patients.Also STAT3 phosphorylation defect could be overcomed by using an alternative pathway the one of Epidermal Growth factor (EGF). Also in one patient its STAT3 defect was overcomed when he entered puberty, sex steroids may enhanced his growth. Objective: The purpose of the study was the characterization of the molecular mechanisms involved in GH signal transduction pathway in GHTD patients, as a possible cause of an increased expression of its inhibitors. Also to search if there is a possible crosstalk between GH and EGF growth transduction pathways. And finally the role of sex steroids in GH signalling in one GHTD patient. Patients/Material and Methods: In primary fibroblast cell cultures from gingival biopsies of the GHTD patients and age-matched normal children we studied: expression analysis, in cells inducted with GH, of CIS and JAK2 phosphorylationby western immunoblotting and RT-PCR. Also the cells of the same children and controls were inducted with EGF and STAT3 phosphorylation was studied. Finally the cells of one of the patients were inducted with GH and 17β-estradiole before and after puberty and its STAT3 phosphorylation and CIS expression were studied. Results: Expression analysis in the childrens’ fibroblasts showed an overexpression of CIS in 2 patients as compared to normal children. STAT3 defect was not present in the patients fibroblasts that were inducted with EGF. Also one GHTD patient that he couldn't phosphorylate in his inducted fibroblast with GH and 17-b estardiole STAT3 and ubiquitinated CIS was present to his cells before puberty this defect was overcomed after he entered puberty. Conclusions: The overexpression of CIS may inhibit the activation of STAT3 and may be involved in the pathogenesis of the severe short stature of the GHTD children. Also GH signalling pathway has no defect in control patients so there is no need of using an alternative pathway such as the one of EGF that occurs in GHTD patients. Also one GHTD patient that showed a STAT3 defect before puberty was overcomed after he entered puberty and without GH treatment. There is a clinical status that is called 'growth dealy' that matches this patients profile, that shows rapid growth after puberty. A probable cause could be that ubiquitinated form of CIS was not present after he entered puberty.
32

Adverse anthropometric risk profile in biochemically controlled acromegalic patients: comparison with an age- and gender-matched primary care population

Dimopoulou, Christina, Sievers, Caroline, Wittchen, Hans-Ulrich, Pieper, Lars, Klotsche, Jens, Roemmler, J., Schopohl, J., Schneider, Harald Jörn, Stalla, Günter K. 21 February 2013 (has links) (PDF)
GH and IGF-1 play an important role in the regulation of metabolism and body composition. In patients with uncontrolled acromegaly, cardiovascular morbidity and mortality are increased but are supposed to be normalised after biochemical control is achieved. We aimed at comparing body composition and the cardiovascular risk profile in patients with controlled acromegaly and controls. A cross-sectional study. We evaluated anthropometric parameters (height, weight, body mass index (BMI), waist and hip circumference, waist to height ratio) and, additionally, cardiovascular risk biomarkers (fasting plasma glucose, HbA1c, triglycerides, total cholesterol, HDL, LDL, and lipoprotein (a), in 81 acromegalic patients (58% cured) compared to 320 age- and gender-matched controls (ratio 1:4), sampled from the primary care patient cohort DETECT. The whole group of 81 acromegalic patients presented with significantly higher anthropometric parameters, such as weight, BMI, waist and hip circumference, but with more favourable cardiovascular risk biomarkers, such as fasting plasma glucose, total cholesterol, triglycerides and HDL levels, in comparison to their respective controls. Biochemically controlled acromegalic patients again showed significantly higher measurements of obesity, mainly visceral adiposity, than age- and gender-matched control patients (BMI 29.5 ± 5.9 vs. 27.3 ± 5.8 kg/m2; P = 0.020; waist circumference 100.9 ± 16.8 vs. 94.8 ± 15.5 cm; P = 0.031; hip circumference 110.7 ± 9.9 vs. 105.0 ± 11.7 cm; P = 0.001). No differences in the classical cardiovascular biomarkers were detected except for fasting plasma glucose and triglycerides. This effect could not be attributed to a higher prevalence of type 2 diabetes mellitus in the acromegalic patient group, since stratified analyses between the subgroup of patients with acromegaly and controls, both with type 2 diabetes mellitus, revealed that there were no significant differences in the anthropometric measurements. Biochemically cured acromegalic patients pertain an adverse anthropometric risk profile, mainly because of elevated adiposity measurements, such as BMI, waist and hip circumference, compared to an age- and gender-matched primary care population.
33

Ανίχνευση μεταλλάξεων του γονιδίου της αυξητικής ορμόνης (GH1) σε παιδιά με κοντό ανάστημα

Παπαθανασοπούλου, Βασιλική Σ. 18 February 2009 (has links)
Η διαδικασία της αύξησης ελέγχεται από έναν πολύπλοκο συνδυασμό πολλών παραγόντων σε διάφορα επίπεδα, που περιλαμβάνουν ενδογενείς παράγοντες, όπως είναι ο γονότυπος, οι ορμόνες, οι παράγοντες αύξησης και εξωγενείς παράγοντες, όπως είναι η διατροφή και η επίδραση του περιβάλλοντος. Οι ορμονικοί παράγοντες, που επηρεάζουν την αύξηση είναι κυρίως η αυξητική ορμόνη (GH) και οι ινσουλινόμορφοι αυξητικοί παράγοντες (IGFs). Στην διαδικασία της αύξησης συμμετέχουν, όμως, και άλλες ορμόνες, όπως η θυροξίνη, τα επινεφριδιακά ανδρογόνα, τα στεροειδή του φύλου, τα γλυκοκορτικοειδή, η βιταμίνη D, η λεπτίνη και η ινσουλίνη, που αλληλεπιδρούν με τον άξονα GH-IGF. Η αυξητική ορμόνη εκκρίνεται στην κυκλοφορία από τα σωματότροπα κύτταρα του πρόσθιου λοβού της υπόφυσης, υπό την επίδραση δύο υποθαλαμικών ορμονών του εκλυτικού παράγοντα της αυξητικής ορμόνης (GHRH), που διεγείρει την έκκριση της GH και της σωματοστατίνης (SS), που αναστέλλει την έκκρισή της. Μέχρι σήμερα στην διεθνή βιβλιογραφία έχουν περιγραφεί πολλές μεταλλάξεις του γονιδίου της GH ως αιτία κοντού αναστήματος στα παιδιά. Η παρούσα μελέτη εξέτασε ομάδα 11 παιδιών με κοντό ανάστημα, ρυθμό αύξησης κάτω από την 2η εκατοστιαία θέση και καθυστερημένη οστική ηλικία. Όλοι οι ασθενείς υπεβλήθησαν σε λεπτομερή κλινική εξέταση και πλήρη εργαστηριακό έλεγχο. Από την κλινική εξέταση και τον εργαστηριακό έλεγχο αποκλείστηκε η παρουσία κάποιας συστηματικής πάθησης. Στην συνέχεια υπεβλήθησαν σε προκλητές δοκιμασίες έκκρισης της GH, με κλονιδίνη και L-Dopa, σε έλεγχο της 24ωρης έκκρισης της GH και τη δοκιμασία γένεσης του IGF-I. Με βάση τα εργαστηριακά αποτελέσματα της έκκρισης της GH η ομάδα των ασθενών διαχωρίστηκε σε αυτούς με ιδιοπαθές κοντό ανάστημα (10 περιπτώσεις) και ένα ασθενή με νευροεκκριτική δυσλειτουργία της GH (GHND), ο οποίος είχε μειωμένη 24ωρη έκκριση GH. Από τους ασθενείς αυτούς ελήφθησαν βιοψίες ούλων, στους καλλιεργημένους ινοβλάστες των οποίων έγιναν οι μελέτες αύξησης των ινοβλαστών και περιφερικό αίμα, από το οποίο έγινε εξαγωγή γονιδιωματικού DNA. Έγινε πολλαπλασιασμός των γονιδίων του υποδοχέα της GH (GHR) και του γονιδίου της GH (GH1) με την αλυσιδωτή αντίδραση πολυμεράσης (PCR) και προσδιορισμός της αλληλουχίας τους. Ανιχνεύτηκαν μεταλλαγές στους 6 από τους 11 ασθενείς, που μελετήθηκαν, οι οποίες εντοπίζονταν στο ιντρόνιο 4 του γονιδίου GH1 και ένας ακόμη ασθενής που έφερε μεταλλάξεις στα ιντρόνια 1 και 2. Οι μεταλλάξεις αυτές δεν επηρέαζαν την διαδικασία του ματίσματος και τον σχηματισμό του mRNA και απομακρύνονταν με το μάτισμα. Στην βιβλιογραφία αναφέρονται περισσότεροι από 10 πολυμορφισμοί του γονιδίου GH1 που εντοπίζονται κυρίως στα ιντρόνια του γονιδίου και κάποιοι από αυτούς έχουν συσχετιστεί με ελαττωμένη έκφραση του γονιδίου GH1. Στον ασθενή με την GHND περιγράφηκε μια μεταλλαγή στη θέση +7 του ιντρονίου 4 του γονιδίου GH1. RT-PCR του GH1 cDNA έδειξε ότι η μετάλλαξη αυτή είναι υπεύθυνη για το εσφαλμένο μάτισμα του mRNA, με αποτέλεσμα την απαλοιφή του εξονίου 5 από το ώριμο μετάγραφο. Ο ασθενής με τη μεταλλαγή είναι ετεροζυγώτης και η ίδια μεταλλαγή σε ετερόζυγη κατάσταση, βρέθηκε και στους δύο γονείς του ασθενούς, οι οποίοι έχουν επίσης κοντό ανάστημα. Η μεταλλαγή αυτή οδηγεί στην παραγωγή μικρότερου μορίου GH. Η βιοδραστικότητα του παραγόμενου ανώμαλου μορίου της GH εκτιμήθηκε με την προσθήκη ορού του ασθενούς σε καλλιέργειες φυσιολογικών ινοβλαστών, με τη μέθοδο ενσωμάτωσης στο DNA της βρώμο-δεοξυουριδίνης (BrDU), η οποία έδειξε μειωμένη σύνθεση DNA συγκρινόμενη με την σύνθεση DNA παρουσία ορού φυσιολογικών ατόμων. Δηλαδή η περίπτωση αυτή οικογενούς κοντού αναστήματος, το οποίο κληρονομείται κατά τον επικρατούντα χαρακτήρα, οφείλεται σε μεταλλαγή στο ιντρόνιο 4 του γονιδίου GH1. / Growth can be defined as an increase in size by accretion of tissue. The control of the growth process is affected by many complex interacting factors including internal cues such as the genotype, external factors such as nutrition and environment, and internal signaling systems such as hormones and growth factors. The principal hormones influencing growth are Growth Hormone (GH) and the Insulin-like Growth Factors (IGFs), but many other hormones contribute, such as thyroxine, adrenal androgens, sex steroids, glucocorticoids, vitamin D, leptin and insulin, often channeled through interaction with the GH-IGF axis. GH is secreted from the anterior pituitary into the circulation. The pattern of GH secretion is determined primarily by the interaction between the hypothalamic peptides Growth Hormone Releasing Hormone (GHRH) and somatostatin (SS). Many mutations of the GH1 gene have been described as the cause of short stature in children. The present study examined 11 children with severe short stature, growth velocity below the 2nd centile and delayed bone age. All patients underwent thorough clinical examination and laboratory investigation in order to exclude an underlying chronic disease. Also GH secretion provocative studies, 24 hr endogenous secretion studies and IGF-I generation test were carried out. According to the results of these tests the patients we studied were divided in two groups: 10 of the patients had idiopathic short stature (ISS) and 1 patient had GH neurosecretory dysfunction (GHND). Fibroblast cultures were established from gingival biopsies obtained from the patients and genomic DNA was extracted from peripheral blood leukocytes. GH1 and GH receptor (GHR) genes were amplified by PCR and sequenced. Hot spot mutations were detected in GH1 intron 4 in 6 patients and mutations in introns 1 and 2 were detected in 1 patient. These mutations did not affect the splicing of the primary RNA transcript. A novel deletion of thymine 7 bp downstream from the 3' splice site of intron 4 was found in the patient who had GHND. RT-PCR of GH1 cDNA showed that this mutation causes aberrant GH mRNA splicing, changes the read frame, creates a new stop codon and results in the deletion of exon 5. This was also confirmed by restriction enzyme analysis of the mutant cDNA. Both short parents and the patient are heterozygotes for this mutation. BrDU incorporation in the DNA of normal fibroblast cultures in the presence of the patient’s blood serum showed reduced DNA synthesis compared to fibroblasts cultured in medium with normal human serum. Addition of high concentrations of GH (4 μg/ml) to the culture medium containing the patient’s serum led to a near normal DNA synthesis. This is a new case of familial short stature inherited as a dominant trait, due to a mutation in intron 4 of the GH1 gene.
34

Implication de l'activité constitutive du récepteur de la ghréline dans la tumorigenèse des adénomes somatotropes / Implication of the constitutive activity of the GHS-R1a in tumorigenesis of somatotroph adenomas

Mear, Yves 20 December 2013 (has links)
Les adénomes hypophysaires sont les tumeurs intracérébrales les plus fréquentes. Les adénomes somatotropes hypersécrètent l’hormone de croissance (GH) et sont traités classiquement par des analogues somatostatinergiques. Une petite moitié des patients acromégales est néanmoins résistante à ces traitements. L’on sait depuis, quelques années, que le récepteur de la ghréline possède une forte activité constitutive et joue un rôle majeur dans la sécrétion de GH. Cette activité constitutive est-elle impliquée dans la tumorigenèse des adénomes somatotropes ? Nos travaux ont montré un niveau de transcrits, codant pour le GHS-R, particulièrement élevé dans ces tumeurs, et l’immunocytochimie révèle un marquage punctiforme localisé à la membrane plasmique. La MSP (agoniste inverse du GHS-R) induit une diminution dose-dépendante de la sécrétion de GH des cultures primaires d’adénomes somatotropes. Cette efficacité de la MSP sur la sécrétion de l’hormone de croissance est particulièrement remarquable sur les patients résistants aux agonistes somatostatinergiques chez qui elle démontre une efficacité relative accrue. Des clones, surexprimant le GHS-R humain (lignées MYST-R), ont été générés à partir de lignées somato-lactotropes tumorales de rat (GH4C1). Sur ces cellules, le ligand endogène du GHS-R induit une augmentation d’IP3 intracellulaire. De façon originale, la MSP induit une diminution du niveau d’IP3 intracellulaire. L’inhibition de l’activité constitutive du GHS-R par un agoniste inverse, tel que la MSP, pourrait permettre de réprimer l’hypersécrétion de GH, faisant de cette molécule une alternative pharmacologique aux traitements actuels des adénomes somatotropes. / Pituitary tumors are most usual intracranial tumors. The somatotroph adenomas are characterised by a GH hypersecretion. The current treatments are based on somatostatinergic agonists. Unfortunately, there is steel 50% of patients, which remain insensitive to these treatments. The aim of our work was to find a pharmacological alternative to treat the patients resistant to the current therapies. Ghrelin stimulate pituitary GH release in vivo through GHS-R1a activation. Interestingly, this receptor transduces signal through an unusual high constitutive activity. Noteworthy, human somatotroph adenomas expressed a high level of GHS-R1a at both mRNA and protein level. We actually assess the implication of this constitutive activity in the tumorigenesis of the somatotroph adenomas. Firstly we demonstrated GHS-R1a functionality through its capacity to fixe endogenous ligand. Then we showed that treatment of human somatotroph adenomas primary cultures, with the GHS-R1a inverse agonist (MSP: Modified Substance P), induced a dose dependent decrease of GH secretion. To foremost investigate the transduction mechanisms underlying these results, we developed, from GH4C1 (rat somato-lactotroph tumoral cell line), stable monoclonal cell lines overexpressing human GHS-R1a (named MYST-Rg). Interestingly MYST-Rg cells exhibit relatively high basal activation of the IP3 pathway. GHS-R1a endogenous ligand (ghrelin) strengthens basal IP3 pathway activation of MYST-Rg cells. Noteworthy, the basal IP3 pathway activation can be lessened by MSP treatment. Thus, MSP could be a useful alternative to the current therapies of somatotroph adenomas.
35

Adverse anthropometric risk profile in biochemically controlled acromegalic patients: comparison with an age- and gender-matched primary care population

Dimopoulou, Christina, Sievers, Caroline, Wittchen, Hans-Ulrich, Pieper, Lars, Klotsche, Jens, Roemmler, J., Schopohl, J., Schneider, Harald Jörn, Stalla, Günter K. January 2010 (has links)
GH and IGF-1 play an important role in the regulation of metabolism and body composition. In patients with uncontrolled acromegaly, cardiovascular morbidity and mortality are increased but are supposed to be normalised after biochemical control is achieved. We aimed at comparing body composition and the cardiovascular risk profile in patients with controlled acromegaly and controls. A cross-sectional study. We evaluated anthropometric parameters (height, weight, body mass index (BMI), waist and hip circumference, waist to height ratio) and, additionally, cardiovascular risk biomarkers (fasting plasma glucose, HbA1c, triglycerides, total cholesterol, HDL, LDL, and lipoprotein (a), in 81 acromegalic patients (58% cured) compared to 320 age- and gender-matched controls (ratio 1:4), sampled from the primary care patient cohort DETECT. The whole group of 81 acromegalic patients presented with significantly higher anthropometric parameters, such as weight, BMI, waist and hip circumference, but with more favourable cardiovascular risk biomarkers, such as fasting plasma glucose, total cholesterol, triglycerides and HDL levels, in comparison to their respective controls. Biochemically controlled acromegalic patients again showed significantly higher measurements of obesity, mainly visceral adiposity, than age- and gender-matched control patients (BMI 29.5 ± 5.9 vs. 27.3 ± 5.8 kg/m2; P = 0.020; waist circumference 100.9 ± 16.8 vs. 94.8 ± 15.5 cm; P = 0.031; hip circumference 110.7 ± 9.9 vs. 105.0 ± 11.7 cm; P = 0.001). No differences in the classical cardiovascular biomarkers were detected except for fasting plasma glucose and triglycerides. This effect could not be attributed to a higher prevalence of type 2 diabetes mellitus in the acromegalic patient group, since stratified analyses between the subgroup of patients with acromegaly and controls, both with type 2 diabetes mellitus, revealed that there were no significant differences in the anthropometric measurements. Biochemically cured acromegalic patients pertain an adverse anthropometric risk profile, mainly because of elevated adiposity measurements, such as BMI, waist and hip circumference, compared to an age- and gender-matched primary care population.
36

Effect of 5-Aza-2´-Deoxycytidine and Trichostatin A on Endogenous Versus Ectopic Expression of Placental Members of the Human Growth Hormone Gene Family

Ganguly, Esha 07 March 2016 (has links)
Background: The genes coding for human (h) chorionic somatomammotropin (CS), hCS-A and hCS-B, and placental growth hormone (GH-V), hGH-V are located at a single locus on chromosome 17q22-24. Local regulatory (5´ P and 3´ enhancer) sequences and a remote locus control region (LCR) containing a placenta-specific hypersensitive site (HS) IV, have been implicated in the efficient expression of the placental hCS/GH-V genes, in part through gene transfer studies in placental and non-placental tumor cell lines. However, low levels of endogenous expression are reported in placental tumor cells compared to normal term placenta. Thus it was hypothesized that the hCS/GH-V chromatin structure in human choriocarcinoma cells is less accessible to regulatory regions essential for efficient expression due to DNA and/or histone modifications, specifically methylation and acetylation, respectively. Approach: To assess individual hCS-A, hCS-B and hGH-V gene expression in placental and non-placental tumor cells, and assess the effect of increasing “chromatin accessibility” on hCS/GH-V RNA levels by inhibiting DNA methylation and histone deacetylation using 5-aza-2´-deoxycytidine (azadC) and trichostatin A (TSA). Principal Findings: Low levels of hCS-A, hCS-B and hGH-V RNA were detected in placental and non-placental tumor cells compared to term placenta. A significant >5-fold increase in promoter activity was seen in placental but not non-placental cells transfected with hybrid hCS promoter luciferase genes containing 3´-enhancer sequences. Placental JEG-3 cells pretreated with azadC and TSA resulted in a significant >10-fold increase in hCS-A, hCS-B and hGH-V RNA levels compared to TSA treatment alone, however, a modest ~3-fold effect was seen in non-placental MCF-7 cells. By contrast to the effect of pretreatment with azadC, post-treatment with azadC mutes the stimulatory effects of TSA on hCS/GH-V transcripts. The specificity of the response suggests that azadC treatment, and presumably hypomethylation of DNA, results in an increase in response to TSA and histone hyperacetylation at the hGH/CS locus. An assessment of histone H3/H4 hyperacetylation in JEG-3 cells treated with azadC and TSA versus TSA alone revealed significant increases consistent with a more open chromatin structure including the hCS 3´-enhancer sequences and LCR. Conclusions: These observations suggest that accessibility of remote and local regulatory regions required for efficient placental hGH/CS expression can be restricted by DNA methylation and histone acetylation status. This includes restricting access of the hCS 3´-enhancer sequences to available placental enhancer transcription factors. / May 2016
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Efeito do polimorfismo do gene do GH e suas relações com os níveis de IGF-1, progesterona e escore corporal, produção de leite e dias em aberto em vacas Holandesas no início da lactação / GH gene?s polymorphism effect and your relationship with IGF-1 levels, progesterone and body condition, milk production and days open in Holstein cows in early lactation

Maranhão, Andréa Mendes 05 December 2003 (has links)
Foram utilizados 60 animais da raça Holandesa, distribuídos em 2 grupos de acordo com número de lactação e em dois tempos de acordo com época de concepção. Para Alu-1, animais com genótipo Leu/Leu apresentaram maior produção de leite na lactação (p = 0,016) e tendência para maior produção ao pico (p = 0,054) que animais do genótipo Leu/Val. Não foi possível demonstrar efeito de genótipo para Dde-1 sobre nenhuma das variáveis estudadas. Houve correlação positiva entre níveis de IGF-1 e P4 (R2 = 0,28 e p = 0,011), correlação negativa entre IGF-1 DEAs, produção na lactação e produção ao pico de lactação (R2=- 0,267 e p = 0,016; R2=- 0,424 e p =0,0001; R2= -0,231 e p=0,0001, respectivamente). Houve tendência de correlação positiva entre escore corporal e níveis de P4 (R2 = 0,216 e p = 0,053). Concluí-se que o polimorfismo do fragmento de restrição identificado pela Alu-1 possa ser utilizado como marcador genético importante para seleção de gado leiteiro, e que o polimorfismo para Dde-1 não se apresentou como um bom marcador genético a ser utilizado para a raça Holandesa, o nível plasmático de IGF-1 parece ser um bom indicador do retorno a atividade reprodutiva. / Sexty female Holstein cows were used in this experiment, animals were arranged random in two groups in agreement lactation number and conception time.Animals with ALU-1 genotipe showed biggest milk production in lactation (p = 0,016) and tendence to biggest milk peak production than Leu/Val animals. Dde-1 didn?t showed genotipe effect for any variavels. There were positive correlactin among IGF-1 and progesterone (R2 =0,280 e p = 0,011). There were negative correlactin among IGF-1 and days open, lactation production, peak lactation (R2=- 0,267 p = 0,016; R2=- 0,424 p =0,0001; R2= -0,231 p=0,0001, respective). There were tendence of positive correlaction (R2 = 0,216 p=0,053) among body condition and progesterone levels. Basead on the results of the experiment, the Alu-1 polymorphism could be used as genetic markers to milk cow selection; DDE-1 polymorphism isnt indicate like genetic marker in Holstein cows; the IGF-1 levels seens a good indicator to return reproduction activite.
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Efeito do polimorfismo do gene do GH e suas relações com os níveis de IGF-1, progesterona e escore corporal, produção de leite e dias em aberto em vacas Holandesas no início da lactação / GH gene?s polymorphism effect and your relationship with IGF-1 levels, progesterone and body condition, milk production and days open in Holstein cows in early lactation

Andréa Mendes Maranhão 05 December 2003 (has links)
Foram utilizados 60 animais da raça Holandesa, distribuídos em 2 grupos de acordo com número de lactação e em dois tempos de acordo com época de concepção. Para Alu-1, animais com genótipo Leu/Leu apresentaram maior produção de leite na lactação (p = 0,016) e tendência para maior produção ao pico (p = 0,054) que animais do genótipo Leu/Val. Não foi possível demonstrar efeito de genótipo para Dde-1 sobre nenhuma das variáveis estudadas. Houve correlação positiva entre níveis de IGF-1 e P4 (R2 = 0,28 e p = 0,011), correlação negativa entre IGF-1 DEAs, produção na lactação e produção ao pico de lactação (R2=- 0,267 e p = 0,016; R2=- 0,424 e p =0,0001; R2= -0,231 e p=0,0001, respectivamente). Houve tendência de correlação positiva entre escore corporal e níveis de P4 (R2 = 0,216 e p = 0,053). Concluí-se que o polimorfismo do fragmento de restrição identificado pela Alu-1 possa ser utilizado como marcador genético importante para seleção de gado leiteiro, e que o polimorfismo para Dde-1 não se apresentou como um bom marcador genético a ser utilizado para a raça Holandesa, o nível plasmático de IGF-1 parece ser um bom indicador do retorno a atividade reprodutiva. / Sexty female Holstein cows were used in this experiment, animals were arranged random in two groups in agreement lactation number and conception time.Animals with ALU-1 genotipe showed biggest milk production in lactation (p = 0,016) and tendence to biggest milk peak production than Leu/Val animals. Dde-1 didn?t showed genotipe effect for any variavels. There were positive correlactin among IGF-1 and progesterone (R2 =0,280 e p = 0,011). There were negative correlactin among IGF-1 and days open, lactation production, peak lactation (R2=- 0,267 p = 0,016; R2=- 0,424 p =0,0001; R2= -0,231 p=0,0001, respective). There were tendence of positive correlaction (R2 = 0,216 p=0,053) among body condition and progesterone levels. Basead on the results of the experiment, the Alu-1 polymorphism could be used as genetic markers to milk cow selection; DDE-1 polymorphism isnt indicate like genetic marker in Holstein cows; the IGF-1 levels seens a good indicator to return reproduction activite.
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Contribution à l'étude des bases moléculaires des maladies de la croissance et du mécanisme de régulation du gène GH chez l'homme

Pérez, Christelle 12 January 2012 (has links) (PDF)
Chez la souris, Six6 et Lhx2 sont exprimés dans l'œil et la glande pituitaire en développement. Par une approche "gènes candidats", les ADN de patients avec un phénotype proche de celui de souris invalidées pour ces gènes ont été séquencés. Aucune mutation a été mise en évidence pour SIX6. Deux variations hétérozygotes faux-sens de LHX2 ont été identifiées mais n'ont pas d'effet (tests in vitro). LHX2 a un rôle régulateur transcriptionnel in vitro sur deux gènes pituitaires (PRL, POU1F1), et en action synergique avec POU1F1. Deux mutations hétérozygotes composites de LHX3 chez un patient non consanguin ont permis d'assigner à ce gène un syndrome décrit uniquement chez des patients consanguins. Une de ces mutations a un effet dominant négatif. POU1F1, impliqué dans la différenciation pituitaire terminale, est associé en pathologie humaine à un déficit en hormone de croissance (GH), PRL et TSHβ. L'expression de GH est régulée par la fixation de POU1F1 sur son promoteur et sur un " Locus Control Region " mais ses cofacteurs ne sont pas connus. Deux mutations faux-sens identifiées dans le domaine de transactivation (TAD) de POU1F1 sont associées à un déficit isolé en GH. La résonnance plasmonique de surface a permis de définir les interactions de POU1F1 (normal et mutés) sur ses séquences cibles ; des extraits nucléaires sont passés avec POU1F1 (normal et mutés) afin d'identifier (par spectrométrie de masse) ses partenaires au locus GH. Une cristallographie du TAD a débuté pour analyser sa structure tridimensionnelle qui est probablement altéré par les mutations identifiées
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Retinal Growth Hormone: An Autocrine/paracrine in the Developing Chick Retina

Lin, Wan-Ying Unknown Date
No description available.

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