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@ARTICLE{Brlin:119673,
      author       = {C. S. Börlin$^*$ and V. Lang$^*$ and A. Hamacher-Brady$^*$
                      and N. Brady$^*$},
      title        = {{A}gent-based modeling of autophagy reveals emergent
                      regulatory behavior of spatio-temporal autophagy dynamics.},
      journal      = {Cell communication and signaling},
      volume       = {12},
      number       = {1},
      issn         = {1478-811X},
      address      = {London},
      publisher    = {Biomed Central},
      reportid     = {DKFZ-2017-00304},
      pages        = {56},
      year         = {2014},
      abstract     = {Autophagy is a vesicle-mediated pathway for lysosomal
                      degradation, essential under basal and stressed conditions.
                      Various cellular components, including specific proteins,
                      protein aggregates, organelles and intracellular pathogens,
                      are targets for autophagic degradation. Thereby, autophagy
                      controls numerous vital physiological and pathophysiological
                      functions, including cell signaling, differentiation,
                      turnover of cellular components and pathogen defense.
                      Moreover, autophagy enables the cell to recycle cellular
                      components to metabolic substrates, thereby permitting
                      prolonged survival under low nutrient conditions. Due to the
                      multi-faceted roles for autophagy in maintaining cellular
                      and organismal homeostasis and responding to diverse
                      stresses, malfunction of autophagy contributes to both
                      chronic and acute pathologies.We applied a systems biology
                      approach to improve the understanding of this complex
                      cellular process of autophagy. All autophagy pathway vesicle
                      activities, i.e. creation, movement, fusion and degradation,
                      are highly dynamic, temporally and spatially, and under
                      various forms of regulation. We therefore developed an
                      agent-based model (ABM) to represent individual components
                      of the autophagy pathway, subcellular vesicle dynamics and
                      metabolic feedback with the cellular environment, thereby
                      providing a framework to investigate spatio-temporal aspects
                      of autophagy regulation and dynamic behavior. The rules
                      defining our ABM were derived from literature and from
                      high-resolution images of autophagy markers under basal and
                      activated conditions. Key model parameters were fit with an
                      iterative method using a genetic algorithm and a predefined
                      fitness function. From this approach, we found that accurate
                      prediction of spatio-temporal behavior required increasing
                      model complexity by implementing functional integration of
                      autophagy with the cellular nutrient state. The resulting
                      model is able to reproduce short-term autophagic flux
                      measurements (up to 3 hours) under basal and activated
                      autophagy conditions, and to measure the degree of
                      cell-to-cell variability. Moreover, we experimentally
                      confirmed two model predictions, namely (i) peri-nuclear
                      concentration of autophagosomes and (ii) inhibitory
                      lysosomal feedback on mTOR signaling.Agent-based modeling
                      represents a novel approach to investigate autophagy
                      dynamics, function and dysfunction with high biological
                      realism. Our model accurately recapitulates short-term
                      behavior and cell-to-cell variability under basal and
                      activated conditions of autophagy. Further, this approach
                      also allows investigation of long-term behaviors emerging
                      from biologically-relevant alterations to vesicle
                      trafficking and metabolic state.},
      keywords     = {Macrolides (NLM Chemicals) / bafilomycin A1 (NLM Chemicals)
                      / MTOR protein, human (NLM Chemicals) / TOR Serine-Threonine
                      Kinases (NLM Chemicals)},
      cin          = {B190},
      ddc          = {610},
      cid          = {I:(DE-He78)B190-20160331},
      pnm          = {312 - Functional and structural genomics (POF3-312)},
      pid          = {G:(DE-HGF)POF3-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:25214434},
      pmc          = {pmc:PMC4172826},
      doi          = {10.1186/s12964-014-0056-8},
      url          = {https://inrepo02.dkfz.de/record/119673},
}