(565e) The Effect of Biological Variability on the Angiotensin II Gene Regulatory Network In the Central Regulation of Blood Pressure

Neurons in the nucleus tractus solitarius (NTS) communicate through chemical messengers to play a major role in blood pressure regulation, and aberrant communications within this brain nucleus cause serious diseases such as hypertension. To fulfill their role in blood pressure regulation, NTS neurons must receive chemical messengers and process these signals through biochemical networks comprising a large number of interacting proteins and genes; but because the population of NTS neurons is heterogeneous, there is significant variability in the abundance and activity of these network components. The effect of this neuron-to-neuron variability on blood pressure regulation is not well-understood and an improvement in understanding is necessary for developing effective treatments of hypertension. Our overall objective, therefore, is to understand how NTS neurons function in the presence of biological variability.

In this work, we investigate the effect of biological variability on a critical mechanism for the central regulation of blood pressure: angiotensin II type 1 receptor (AT1R) activation of tyrosine hydroxylase in the brain. Using the regulatory mechanisms established in the literature (Veerasingham and Raizada, 2003), we construct a mechanistic, ordinary differential equation model for the induction of tyrosine hydroxylase gene expression modulated by the gene regulatory network activated by AT1R. This model allows us to explore the effect of biological variability on neuron function by performing model simulations with variations in reaction rate constants and species initial concentrations, and then comparing the predicted response of tyrosine hydroxylase from AT1R gene networks with variations in model parameters.

We present simulation results showing AT1R activation induces tyrosine hydroxylase robustly in the presence of biological variability, and discuss properties of the AT1R gene regulatory network that ensure this robust performance. By finding this critical mechanism for the central regulation of blood pressure to be robust to neuron-to-neuron variability, our results may lead to the development of improved treatments of hypertension.

Reference

Veerasingham S.J. & Raizada M.K. (2003) Brain renin?angiotensin system dysfunction in hypertension: recent advances and perspectives. Br. J. Pharmacol. 139(2):191-202.