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Title: Quantitative assessment of biological impact using transcriptomic data and mechanistic network models

Exposure to biologically active substances such as therapeutic drugs or environmental toxicants can impact biological systems at various levels, affecting individual molecules, signaling pathways, and overall cellular processes. The ability to derive mechanistic insights from the resulting system responses requires the integration of experimental measures with a priori knowledge about the system and the interacting molecules therein. We developed a novel systems biology-based methodology that leverages mechanistic network models and transcriptomic data to quantitatively assess the biological impact of exposures to active substances. Hierarchically organized network models were first constructed to provide a coherent framework for investigating the impact of exposures at the molecular, pathway and process levels. We then validated our methodology using novel and previously published experiments. For both in vitro systems with simple exposure and in vivo systems with complex exposures, our methodology was able to recapitulate known biological responses matching expected or measured phenotypes. In addition, the quantitative results were in agreement with experimental endpoint data for many of the mechanistic effects that were assessed, providing further objective confirmation of the approach. We conclude that our methodology evaluates the biological impact of exposures in an objective, systematic, and quantifiable manner, enabling the computation of a systems-widemore » and pan-mechanistic biological impact measure for a given active substance or mixture. Our results suggest that various fields of human disease research, from drug development to consumer product testing and environmental impact analysis, could benefit from using this methodology. - Highlights: • The impact of biologically active substances is quantified at multiple levels. • The systems-level impact integrates the perturbations of individual networks. • The networks capture the relationships between the biological mechanisms. • Four exposure experiments have been assessed to validate the methodology. • The impact results were consistent with the corresponding phenotypic measures.« less
Authors:
 [1] ;  [2] ; ;  [2] ;  [1] ;  [3] ;  [1] ;  [3] ;  [2] ; ;  [1] ; ;  [2]
  1. Selventa, One Alewife Center, Cambridge, MA 02140 (United States)
  2. Philip Morris International R and D, Philip Morris Products S.A., Quai Jeanrenaud 5, 2000 Neuchâtel (Switzerland)
  3. Philip Morris International R and D, Philip Morris Research Laboratories GmbH, Edmund-Rumpler-Strasse 5, 51149 Koeln (Germany)
Publication Date:
OSTI Identifier:
22285477
Resource Type:
Journal Article
Resource Relation:
Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 272; Journal Issue: 3; Other Information: Copyright (c) 2013 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; CONSUMER PRODUCTS; DISEASES; DRUGS; ENVIRONMENTAL IMPACTS; IN VITRO; IN VIVO; MOLECULES; PHENOTYPE