Reconstruction of in vivo time-evolving neuroendocrine dose-response properties unveils admixed deterministic and stochastic elements

Daniel Keenan, Susan Alexander, Clifford Irvine, Iain Clarke, Christopher Scott, Anne Turner, Alan Tilbrook, Benedict Canny, Johannes Velhduis

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

Homeostasis in the intact organism is achieved implicitly by repeated incremental feedback (inhibitory) and feedforward (stimulatory) adjustments enforced via intermittent signal exchange. In separated systems, neurohormone signals act deterministically on target cellsvia quantifiable effector'response functions. On the other hand, invivo interglandular signaling dynamics have not been estimable todate. Indeed, experimentally isolating components of an interactive network definitionally disrupts time-sensitive linkages. We implement and validate analytical reconstruction of endogenous effector'response properties via a composite model comprising (i) a deterministic basic feedback and feed forward ensemble structure; (ii) judicious statistical allowance for possible stochastic variability in individual biologically interpretable dose'response properties; and (iii) the sole data requirement of serially observed concentrations of a paired signal (input) and response (output). Application of this analytical strategy to a prototypical neuroendocrine axis in the conscious uninjected horse, sheep, and human (i) illustrates probabilistic estimation of endogenous effector dose'response properties; and (ii)unmasks statistically vivid (2- to 5-fold) random fluctuations in inferred target'gland responsivity within any given pulse train. In conclusion, balanced mathematical formalism allows one to (i) reconstruct deterministic properties of interglandular signaling in the intact mammal and (ii) quantify apparent signal'response variability overshort time scales in vivo. The present proof-of-principle experiments introduce a previously undescribed means to estimate time-evolving signal'response relationships without isotope infusion or pathway disruption
Original languageEnglish
Pages (from-to)6740-6745
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number17
DOIs
Publication statusPublished - 2004

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