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The Balance of Gs and Gi Signaling in Fibroblasts and Cardiomyocytes Affecting Cardiac (Patho-)Physiology
The sympathetic and the parasympathetic axes of the autonomic nervous system regulate cardiac (patho-) physiology by releasing noradrenaline, activating β receptors and Gs signaling, or by releasing acetylcholine, activating muscarinic M2 receptors and Gi signaling. Our overarching objective is to understand how the interplay and balance of Gs and Gi signaling in cardiomyocytes and fibroblasts mediate the effects of the autonomic nervous system on cardiac (patho‑) physiology. We will use complementary in vitro and intact heart analyses by combining the expertise of the Crocini lab in generating human cardiomyocytes, fibroblasts and engineered heart tissues from human induced pluripotent stem cells with the expertise of the Sasse lab in application and functional investigation of light-sensitive receptors in mouse hearts.
Using selective, localized and precisely timed optogenetic activation of Gs and Gi signaling in cardiomyocytes of the sinus node, atrium and ventricular myocardium, we aim to identify antagonistic and synergistic effects and the hierarchy of Gs and Gi signaling on whole heart physiology and cardiac arrhythmia. Furthermore, we will develop a novel fusion protein for dual color Gs and Gi signaling to determine the spatial and temporal extent of local signaling and the (patho-)physiology of non-uniform imbalanced Gs and Gi stimulation.
Because cardiac fibroblasts express many Gs- and Gi-coupled receptors, we will optogenetically activate these signaling cascades in human fibroblasts and determine the effect on induction or prevention of fibrosis signaling. To investigate a potential intercellular communication from fibroblasts to cardiomyocytes, we will optogenetically stimulate Gs and Gi signaling selectively in fibroblasts of human engineered heart tissues and of transgenic mouse hearts and measure effects on cardiac function. Thereby, we aim to understand if Gs or Gi signaling in fibroblasts affects cardiac function through paracrine effects or by cell-cell coupling. Such an intercellular cross talk may represent an important regulatory mechanism of the autonomic nervous system, particularly in the fibrotic heart.
