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Quantitative Analysis of the Gene Regulatory Network Activated by Angiotensin II in the Brain

G Miller, B Ogunnaike, J Schwaber, R Vadigepalli

Angiotensin II type 1 receptor (AT1R) signaling plays an integral role in the synthesis of norepinephrine, a neurotransmitter involved in central cardiovascular regulation. Dysregulation of AT1R signaling within the brain is associated with diseases such as hypertension. AT1R activation affects norepinephrine through a gene regulatory network in which the activated AP-1 family of transcription factors induces expression of tyrosine hydroxylase (TH). However, the dynamics of network components and relative contributions of AP-1 dimers remain unknown. Here, we take a computational modeling approach to investigate the quantitative role of network components on TH gene regulation. Our model simulations predict that AT1R activates a dynamic balance of distinct AP-1 dimers. Model analysis identifies critical mechanisms underlying AP-1 activation, and generates experimentally testable predictions. These results provide quantitative insights into system-wide blood pressure control mechanisms.

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