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@ARTICLE{Mainz:179297,
      author       = {L. Mainz and M. A. F. E. Sarhan and S. Roth and U. Sauer
                      and C. Kalogirou and M. Eckstein and E. Gerhard-Hartmann and
                      H.-D. Seibert and H.-U. Voelker and C. Geppert and A.
                      Rosenwald and M. Eilers and A. Schulze$^*$ and M.
                      Diefenbacher and M. T. Rosenfeldt},
      title        = {{A}cute systemic knockdown of {A}tg7 is lethal and causes
                      pancreatic destruction in sh{RNA} transgenic mice.},
      journal      = {Autophagy},
      volume       = {18},
      number       = {12},
      issn         = {1554-8627},
      address      = {Abingdon, Oxon},
      publisher    = {Taylor $\&$ Francis},
      reportid     = {DKFZ-2022-00579},
      pages        = {2880-2893},
      year         = {2022},
      note         = {2022 Dec;18(12):2880-2893},
      abstract     = {The notion that macroautophagy/autophagy is a potentially
                      attractive therapeutic target for a variety of diseases,
                      including cancer, largely stems from pre-clinical mouse
                      studies. Most of these examine the effects of irreversible
                      and organ confined autophagy deletion using site specific
                      Cre-loxP recombination of the essential autophagy regulating
                      genes Atg7 or Atg5. Model systems with the ability to impair
                      autophagy systemically and reversibly at all disease stages
                      would allow a more realistic approach to evaluate the
                      consequences of authophagy inhibition as a therapeutic
                      concept and its potential side effects. Here, we present
                      shRNA transgenic mice that via doxycycline (DOX) regulable
                      expression of a highly efficient miR30-E-based shRNA enabled
                      knockdown of Atg7 simultaneously in the majority of organs,
                      with the brain and spleen being noteable exceptions. Induced
                      animals deteriorated rapidly and experienced profound
                      destruction of the exocrine pancreas, severe hypoglycemia
                      and depletion of hepatic glycogen storages. Cessation of DOX
                      application restored apparent health, glucose homeostasis
                      and pancreatic integrity. In a similar Atg5 knockdown model
                      we neither observed loss of pancreatic integrity nor
                      diminished survival after DOX treatment, but identified
                      histological changes consistent with steatohepatitis and
                      hepatic fibrosis in the recovery period after termination of
                      DOX. Regulable Atg7-shRNA mice are valuable tools that will
                      enable further studies on the role of autophagy impairment
                      at various disease stages and thereby help to evaluate the
                      consequences of acute autophagy inhibition as a therapeutic
                      concept.},
      keywords     = {Atg5 (Other) / Atg7 (Other) / autophagy (Other) / liver
                      (Other) / pancreas (Other) / shRNA transgenic mice (Other)},
      cin          = {A410},
      ddc          = {570},
      cid          = {I:(DE-He78)A410-20160331},
      pnm          = {311 - Zellbiologie und Tumorbiologie (POF4-311)},
      pid          = {G:(DE-HGF)POF4-311},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:35343375},
      doi          = {10.1080/15548627.2022.2052588},
      url          = {https://inrepo02.dkfz.de/record/179297},
}