TY - JOUR
T1 - Dynamic responses of the adrenal steroidogenic regulatory network
AU - Spiga, Francesca
AU - Zavala, Eder
AU - Walker, Jamie J.
AU - Zhao, Zidong
AU - Terry, John R.
AU - Lightman, Stafford L.
PY - 2017/8/1
Y1 - 2017/8/1
N2 - The hypothalamic–pituitary–adrenal axis is a dynamic system regulating glucocorticoid hormone synthesis in the adrenal glands. Many key factors within the adrenal steroidogenic pathway have been identified and studied, but little is known about how these factors function collectively as a dynamic network of interacting components. To investigate this, we developed a mathematical model of the adrenal steroidogenic regulatory network that accounts for key regulatory processes occurring at different timescales. We used our model to predict the time evolution of steroidogenesis in response to physiological adrenocorticotropic hormone (ACTH) perturbations, ranging from basal pulses to larger stress-like stimulations (e.g., inflammatory stress). Testing these predictions experimentally in the rat, our results show that the steroidogenic regulatory network architecture is sufficient to respond to both small and large ACTH perturbations, but coupling this regulatory network with the immune pathway is necessary to explain the dissociated dynamics between ACTH and glucocorticoids observed under conditions of inflammatory stress.
AB - The hypothalamic–pituitary–adrenal axis is a dynamic system regulating glucocorticoid hormone synthesis in the adrenal glands. Many key factors within the adrenal steroidogenic pathway have been identified and studied, but little is known about how these factors function collectively as a dynamic network of interacting components. To investigate this, we developed a mathematical model of the adrenal steroidogenic regulatory network that accounts for key regulatory processes occurring at different timescales. We used our model to predict the time evolution of steroidogenesis in response to physiological adrenocorticotropic hormone (ACTH) perturbations, ranging from basal pulses to larger stress-like stimulations (e.g., inflammatory stress). Testing these predictions experimentally in the rat, our results show that the steroidogenic regulatory network architecture is sufficient to respond to both small and large ACTH perturbations, but coupling this regulatory network with the immune pathway is necessary to explain the dissociated dynamics between ACTH and glucocorticoids observed under conditions of inflammatory stress.
UR - http://www.scopus.com/inward/record.url?eid=2-s2.0-85026518597&partnerID=MN8TOARS
UR - https://ore.exeter.ac.uk/repository/handle/10871/28717
U2 - 10.1073/pnas.1703779114
DO - 10.1073/pnas.1703779114
M3 - Article
SN - 1091-6490
VL - 114
SP - E6466-E6474
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 31
ER -