Pancreatic Beta-Cells
Pancreatic beta-cells secret insulin in response to elevated blood glucose. Secretion is pulsatile and studies show that body uses insulin more efficiently when the insulin signal is oscillatory. Oscillations are driven by bursts of electrical activity. ATP sensitive potassium channels (K(ATP) channels) play a significant role in the process. A defect in the genes coding these channels leads to Persistent Hyperinsulinemic Hypoglycemia of Infancy (PHHI) in humans, a condition characterized by excessive insulin secretion even when blood glucose is low. However, in genetically engineered SUR1-/- mice, which do not have K(ATP) channels, oscillations persist and these mice exhibit normal blood glucose levels. In these mice compensation must occur to overcome the loss of K(ATP) channels. I am working on mathematical models of compensatory mechanisms to explain the bursting electrical activity observed in SUR1-/- mice pancreatic beta cells.
Ca2+ Signaling and Activity Dependent Gene Expression
Calcium (Ca2+) transmits intracellular information and regulates several cellular processes in many excitable and non-excitable cells. It is important to understand, how such a simple ion can regulate such diverse array of cellular processes. The answer to this question is the wide spatial and temporal distribution of the Ca2+ signal. In gene transcription networks, it is shown that, oscillatory Ca2+ is more effective in regulating gene expression than constant Ca2+. Further more, for certain genes, there seems to be an optimum range of oscillation frequencies in which the signal is most efficient. In these networks, Ca2+ regulates gene expression by acting on transcription factors through enzymes. Dynamic properties of these enzymes and transcription factors make expression frequency dependent. I am investigating network motifs those can keep track of the cellular activity, which is encoded in the Ca2+ signal, and respond to changes by regulating gene expression. I am also interested in modeling activity dependent regulation of gene expression, which may account for the restoration of homeostasis in case of genetic defects or malfunctioning. |
