Description du sujet de thèse

'Role of a novel SERCA3-dependent calcium signaling pathway in the heart.'

Contexte de travail

The Paris-Saclay Neuroscience Institute (NeuroPSI) is located on the CEA site in Saclay. NeuroPSI comprises 21 research teams, platforms and technical services enabling the study of brain function in several animal models at all levels. The PhD student position will be in the 'Astrocytes & Cognition' team, co-directed with Ana Maria Gomez's laboratory (UMR-S 1180 'Ignalisation and Cardiovascular Physiopathology', Univ Paris-Saclay). The cardiovascular system relies on complex calcium signalling, which is essential for cardiac contraction, vascular tone and endothelial and platelet activation. This signalling, whose alterations are implicated in numerous pathologies (hypertrophy, heart failure, atherosclerosis, hypertension), depends in particular on the activity of SERCA pumps. We have recently identified a new calcium signalling pathway, involving the mobilisation of Ca²⁺ via the NAADP messenger from intracellular stores filled by SERCA3. This pathway is necessary for platelet activation and could also play a role in the heart, where SERCA3 is co-expressed with SERCA2 but localised in specific microdomains (intercalary discs, nuclear periphery), suggesting a function in excitation-transcription coupling. TPC channels (1 and 2), targets of NAADP, are expressed in the heart and their inhibition prevents deleterious post-ischaemic calcium oscillations. Our data show that mice deficient in TPCs or SERCA3 display similar cardiac dysfunctions, suggesting a common role in a critical calcium signalling pathway. We will also investigate the source of NAADP. Although CD38 has been proposed as the producing enzyme, our data point to another enzyme expressed in the heart and diaphragm as an alternative source of NAADP. We will therefore test this alternative pathway in cardiovascular cells, using a combination of genetic and functional approaches.