(A-9) A computational model to understand the role of calcium activity in the zebrafish tailfin wound healing process.

The human body is regulated by signals that assist us to perform both voluntary and involuntary activities. Calcium as the second messenger plays a vital role in stimulus-response reactions and other complex biological pathways, one such process is wound healing. the early wound detection process extends all the way from subcellular to organ level scale with the Damage Associated Molecular Patterns (DAMPs) and calcium signaling. A zebrafish fin comprises epithelial cells, and the damaged epithelial cells send signals to the nearby cells. The cascade of events that trigger calcium signaling starts with an agonist binding to the receptors on the surface of the cell membrane to activate them. The activated cell surface receptor (Glycoprotein Coupled Receptors (GPCRs)) activates the Phospholipase C, which is involved in the process of breaking down phosphatidylinositol 4,5-bisphosphate (PIP2) into diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). The IP3 produced from this process further advances to the endoplasmic reticulum of the cell and interacts with the IP3 Receptors (IP3R), thereby inducing calcium release in the endoplasmic reticulum. The calcium flux within the cell is regulated by the exchange of calcium between the endoplasmic reticulum and cytoplasm by the SERCA pump and the IP3R. These cascades of events occur across the whole tissue giving rise to a wave. Previous studies on this same concept revolved around reproducing a drosophila wing disc system and changing the parameters to make it complement the zebrafish system. However, the system could not provide a similar response as observed in experiments. Comprehensive studies revealed a different pattern of calcium activity from the wounded epithelial cells in zebrafish, with potential involvement of DAMPs. Therefore, this study aims to understand the involvement of extracellular calcium and ATP (Adenosine Triphosphate) in the form of DAMPs to trigger these events as an agonist. In the due process, an ordinary differential equation (ODE)--based computational model will be developed across multiple scales to simulate the calcium wave induced by the ATP molecules and their derivatives. The equations used in this model, for purinergic receptors and ATPs, are developed by Huang et al., 2021 and for the GPCRs, PLC, IP3, and calcium are referred to by Politi et al., 2006 and Zartman et al., 2021. Once the equations are obtained and validated, they are expected to be imported to CompuCell3D. It is employed to perform virtual cell and tissue modeling. Like the previously modeled version, this model is also expected to have the same metrics, interactions, and reactions but with an addition of purinergic receptors in the presence of extracellular calcium and ATP derivatives. In addition to the experimental validation, this model will also be validated by quantifying the calcium intensity patterns obtained from the in vivo image data.