08​ – E Camerer Group

Aims

The Camerer group studies G protein-Coupled Receptor (GPCR) signaling in development and disease. Serine proteases and bioactive lipids play important roles during embryonic development that are mediated by dedicated GPCRs. Although our understanding of these GPCR families is rapidly evolving, much remains to be known about how they help coordinate vascular development and to what extent they also regulate vascular homeostasis and/or contribute to vascular disease if deregulated. Our group explores the functional domains of protease-activated receptors (PARs) and sphingosine-1-phospate receptors (S1PRs), their mechanisms of action and their interactions during development and disease. To do so, we seek to identify the sources and repertoires of their agonists to understand how and when they are mobilized, their downstream coupling to understand what messages they transmit, and the effect of gain and loss of function on cell behavior and organ function to understand their interactions and biological roles. We are particularly interested in how these receptor families work together to regulate vascular, epithelial and feto-maternal barriers. 

Approximately one third of all approved drugs target GPCRs, and both PARs and S1PRs are targets for drugs in clinical use. Our research aims to discover new applications for these and other emerging drugs in the field and to inform on how therapeutic targeting of PARs and S1PRs can be refined to improve efficacy and limit side effects.  

Recent Achievements

Addressed protective actions of S1P signalling in the microvasculature, we recently demonstrated that S1PR1 plays a non-redundant role in maintaining vascular integrity and regulating blood flow in the brain. This function becomes essential during cerebral ischemia, where endothelial S1PR1 deficiency strongly exacerbated outcome in mouse models of ischemic stroke. Cell-autonomous S1P provision was required for S1PR1 engagement in this context, as S1P localized on the abluminal side of brain capillaries and therefore did not encounter circulating ligand. Protective actions of S1PR1 could be harnessed with blood-brain barrier penetrating agonists. This study highlighted the critical function for the endothelium in maintaining microvascular perfusion in the ischemic cerebral cortex. 
• Nitzsche et al. Endothelial S1P1 Signaling Counteracts Infarct Expansion in Ischemic Stroke. Circulation Research 2021, 128:363-82 (Commented in Reeson and Brown, Circulation Research 2021, 128:383-85; Anja Nitzsche received the 2020 Bernd Binder publication Award for her contribution)

In order to assess the safety of targeting of S1PR1 therapeutically to improve vascular function, we revisited the role of S1P signalling in platelet biology. Our observations contested the prevailing model, which attributed a critical role to S1PR1 in blood sensing by megakaryocytes and in amplification of thrombosis downstream of conventional platelet activators. Instead, they pointed to previously unappreciated roles for S1P signaling during platelet formation. Consistent with observations in the clinic, our findings argue that therapeutic strategies under development to target S1PR1 for immune suppression and vascular protection are unlikely to increase the risk of bleeding or thrombosis.  
·      Niazi H et al. Murine platelet production is suppressed by S1P release in the hematopoietic niche, not facilitated by blood S1P sensing. Blood Adv. 2019, 11;3(11):1702-1713