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Characterization of the receptors involved in adrenomedullin clearance in the lungs

Fu, Yan (2008). Characterization of the receptors involved in adrenomedullin clearance in the lungs Thèse. Québec, Université du Québec, Institut National de la Recherche Scientifique, Doctorat en biologie, 202 p.

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Résumé

La transcription des symboles et des caractères spéciaux utilisés dans la version originale de ce résumé n’a pas été possible en raison de limitations techniques. La version correcte de ce résumé peut être lue en PDF.

Adrenomedullin (AM), a 52-amino acid peptide, is mostly produced in adrenal, lung, kidney, and heart tissues. The main physiological action of AM appears to be as a potent vasodilator. So far, AM was shown to bind to two different receptor subtypes, AM1. produced by the association of the calcitonin-receptor-like receptor (CLR) and the receptor-activity-modifying protein 2 (RAMP2) and AM 2, obtained by linking CLR to RAMP3. No significant physiological differences upon activation of the AM1 and AM 2 receptors were identified, thus the functional significance of this receptor redundancy remains unclear. Receptor binding studies revealed that the greatest density of AM binding sites in a variety of rat tissues was in the heart and lungs. Hence, this peptide is weil designed to be a lead compound for the development of imaging radiopharmaceuticals of these organs. Currently, only one agent is used in clinical imaging of the pulmonary circulation: 99mTc­ macroaggregated albumin (MAA). However, this agent is lm•ger than most small pulmonary vessels. As a result, the central problem about MAA in the clinical imaging application is its limited sensitivity to investigate small vascular defects. To provide a more powerful tool for diagnostic purposes and for monitoring the treatment responses in the 1ung system, we proposed a 99mTc de1ivery system with 1ung specifiC targeting ligands. The proposed system maximizes the uptake of the 99mTc-complex by the pulmonary system and enhances the influx as weil as retention of the complex in the Jung. This delivery system includes three main components: 99m-technetium, a carrier of the 99mTc, and a targeting moiety. Thus, we have designed a series of AM derivatives and the results of our evaluations showed that 99mTc-linear AM, a system that utilizes 99mTc as the radiation source and AM as a carrier and a targeting moiety (ligand), displayed a clear image of the pulmonary circulation through AM receptors that appear to be acting as clearance receptors. To pursue our study, we have performed binding assays to characterize AM binding sites in dog Jung homogenates. First, we observed that the non selective agonist AM bound with high affinity, displaying two binding sites. Moreover, competition bi nding assays using 5 1-AM and somc unlabeled ligands showed the following rankin g fo r displacement: AM > AM( 13-52) > CGRP ;::: AM2 ;::: AM(22-52) ;::: AM2( 16-47) > CGRP(S-37) >AMY. Thus, these results strongly suggest that the AM binding site found in the dog lungs is mainly the AM 1 receptor subtype. Receptor specifie imaging provides a powerful asset for clinical applications and biological research. Since AM is a long peptide with 52 amino acids, further studies are pursued using AM fragments of various lengths. By determining the amino acids, the minimal peptide fragment, and some relative secondary structures of AM retaining good affinity for the AM receptors in the dog Jung, it will facilitate the identification of the pharmacophores underlying AM 1 binding affinity and specificity. Those information are essen ti al for the discovery of a selective probe for AM 1 receptors. Furthermore, they will help in the development of better and smaller Jung-specifie diagnostic and/or therapeutic molecules after radiopharmaceutical optimization.

Type de document: Thèse
Directeur de mémoire/thèse: Fournier, Alain
Co-directeurs de mémoire/thèse: Dupuis, Jocelyn (Université de Montréal)
Informations complémentaires: Résumé avec symboles
Mots-clés libres: adrenomedulline ; poumon ; calcitonine
Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 25 sept. 2013 18:12
Dernière modification: 08 déc. 2015 15:13
URI: http://espace.inrs.ca/id/eprint/207

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