Using A Systems Biology Approach To Explore Hypotheses Underlying Clinical Diversity Of The Renin Angiotensin System And The Response To Antihypertensive Therapies

In this chapter, we discuss how a systems biology approach can be used in drug development, by presenting an example of building and parameterizing a model of the renin angiotensin system (RAS) pathway. The RAS plays a pivotal role in regulating blood pressure (BP) and kidney function. We introduce a mathematical representation of the pathway in the systemic circulation and describe how we derived the parameters of the model from available clinical measurements and inferences about the homeostatic nature of the physiological system. The chapter includes a brief introduction to the implementation of RAS-modulating therapies, model validation and variability at the pathway level. The chapter also describes the process of extending the model from the systemic circulation to the kidney and the process by which the two models were connected. The work presented here is part of one regulatory pathway in a larger physiological model of BP regulation and renal function (in both healthy and disease states) that is used to generate and test hypotheses of the underlying physiology to investigate a range of clinical scenarios.