In human physiology, the rapid and coordinated secretion of PTH by the parathyroid gland is essential for maintaining healthy levels of serum calcium. Small decrements in serum calcium concentration are routinely demonstrated to produce five to ten fold increases in serum parathyroid concentrations within a few minutes. The extracellular calcium binding to a calcium sensing receptor is thought to inhibit the exocytosis of stored parathyroid hormone into the intercellular spaces. In vitro PTH secreting cells (chief cells) are reported to exhibit greater calcium sensitivity (inhibition of PTH release) when they exist as isolated single cells in comparison to when residing in a connected group of cells: suggesting that a network has emergent regulatory properties. In an adenoma, the parathyroid secreting cells (chief cells) are large and densely packed, the calcium receptor number is diminished, and the PTH secretion per cell is much higher than in healthy tissue. Calcium ions regulatory effect on the secretion of PTH is significantly dampened in adenomatous tissue. The sensitivity of the cells is substantially recovered however, when the adenoma is dispersed into smaller cellular collections. We posit that gland geometry and interstitial PTH in combination alter the interstitial diffusion of calcium and endow the cell network with the capacity for dynamic secretory responses. In order to explore this hypothesis, a series of computational and mathematical models will be constructed. The models will investigate the calcium-PTH physiology, both in the context of small cellular networks as well as the macro physiological scale of organ level responses corresponding to published animal and human clinical experiments. The objective of this proposal is to construct higher-level quantitative models: by using realistic geometric structures, and careful addition of cellular and biophysical processes. In a broader view, our preliminary results suggest that in addition to the cellular mechanisms, glandular networks may have regulatory prowess at the level of interstitial transport.
| Kurtz, I; Petrasek, D; Tatishchev, S (2004) Molecular mechanisms of electrogenic sodium bicarbonate cotransport: structural and equilibrium thermodynamic considerations. J Membr Biol 197:77-90 |
