Objective
Serotonin (5-hydroxytrypatmine, 5-HT) regulates diverse processes in both the central nervous system (e.g. cognition, perception, mood, feeding behaviour) and the periphery (e.g. smooth muscle contractility, platelet aggregation). As such, dysregulation in the 5-HT system has been shown to contribute to several pathophysiological states, including depression, migraine headaches, and, more recently, some cardiovascular diseases.
During my thesis research with Bryan Roth, we demonstrated that 5-HT, the level s of which are elevated in carcinoid syndrome, causes heart valve fibrosis (i.e. cardiac valvulopathy) via activation of 5-HT2B receptors. An additional cardiovascular complication stemming from 5-HT levels is pulmonary hypertension (PH). Prof. Maroteaux has shown, using genetic and pharmacological approaches, that functional 5-HT2B receptors are required for the development of PH in the hypoxic mouse model of the disease. Also, Prof. Maroteaux's in vivo studies have shown that decreased 5-HT2B receptor function prevents hypoxia-induced increases in plasma 5-HT. Thus, 5-HT2B receptors appear to play an unappreciated role in 5-HT synthesis, release, and/or uptake in the cardiovascular system and likely elsewhere (e.g. the CNS).
Indeed, preliminary findings from Prof. Maroteaux's group reveal a role for 5-HT2B receptors in the plasma membrane targeting of the 5-HT transporter (SERT), suggesting that 5-HT2B receptors affect 5-HT levels by modulating SERT function. Thus, Prof. Maroteaux and I propose to characterize, through in vitro and tissue-specific in vivo studies, the mechanism of 5-HT2B receptors regulate SERT function and 5-HT levels in the cardiovascular system. These studies are likely to uncover previously unidentified mechanisms regulating 5-HT in the cardiovascular system; mechanisms that may be pertinent in the CNS. As such, our efforts could lead to novel strategies to treat cardiovascular diseases and, possibly, psychiatric disorders.
Fields of science
Call for proposal
FP6-2004-MOBILITY-7
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Funding Scheme
IIF - Marie Curie actions-Incoming International FellowshipsCoordinator
PARIS
France