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Title: Physiology of NAADP : insights from in silico and in vitro studies
Author: Vasudevan, Sridhar Ramaswamy
ISNI:       0000 0001 3543 2581
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2008
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In this thesis, I have explored the physiological role and the mode of synthesis of the Ca2-'--releasing second messenger, Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP). I demonstrate ill my work, the presence of a NAADP synthesizing enzyme; NAADP synthase, that is specific for NAADl> production and is regulated by Ca2+. This was demonstrated with use of biochemical, HPLC and confocal microscopy techniques. Followed by this, I show the ability ofNAADP to release Ca2 -!- from sea urchin spenn. As an extension to this study, I demonstrate the presence of NAADP-binding sites and explore the nature of the NAADP-sensitive Ca2 -!- stores involved. This study was conducted using techniques such as 4$Ca2-:- flux assays, Mn2 .,.-quench assays, e2p]NAADP binding assays and confocal microscopy. In the third part ofmy study, I study the possibility of NAADP being an endogenous cellular messenger in neurons by studying its ability to release Cal -'- using confocal microscopy, electroporation and phannacological studies. These results provide comprehensive insights into the roles of NAADP in CaZ+ signalling, the nature of the· stores NAADP acts upon and the nature of its receptor in a range of cell types such as in spenn as well as neurons. Research on NAADP signalling would benefit greatly from the development of pharmacological modulators ofNAADP signalling cascade. As no such molecules are available, in the final part ofmy study, I make USe of computer-aided drug design to develop novel phaImacological tools to modulate NAADP signalling. I have developed, thus far, an NAADP-receptor antagonist, an NAADP·phosphatase inhibitor and a partial agonist for inositol·l,4,S-trisphosphate-receptor. These successes have added greatly to our toolkit for NAADP research and possibly to nlture dmg discovery efforts.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available