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000179297 041__ $$aEnglish
000179297 082__ $$a570
000179297 1001_ $$aMainz, Laura$$b0
000179297 245__ $$aAcute systemic knockdown of Atg7 is lethal and causes pancreatic destruction in shRNA transgenic mice.
000179297 260__ $$aAbingdon, Oxon$$bTaylor & Francis$$c2022
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000179297 500__ $$a2022 Dec;18(12):2880-2893
000179297 520__ $$aThe 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.
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000179297 650_7 $$2Other$$aAtg5
000179297 650_7 $$2Other$$aAtg7
000179297 650_7 $$2Other$$aautophagy
000179297 650_7 $$2Other$$aliver
000179297 650_7 $$2Other$$apancreas
000179297 650_7 $$2Other$$ashRNA transgenic mice
000179297 7001_ $$aSarhan, Mohamed A F E$$b1
000179297 7001_ $$aRoth, Sabine$$b2
000179297 7001_ $$aSauer, Ursula$$b3
000179297 7001_ $$aKalogirou, Charis$$b4
000179297 7001_ $$aEckstein, Markus$$b5
000179297 7001_ $$aGerhard-Hartmann, Elena$$b6
000179297 7001_ $$aSeibert, Helen-Desiree$$b7
000179297 7001_ $$00000-0003-0610-2254$$aVoelker, Hans-Ulrich$$b8
000179297 7001_ $$aGeppert, Carol$$b9
000179297 7001_ $$aRosenwald, Andreas$$b10
000179297 7001_ $$aEilers, Martin$$b11
000179297 7001_ $$0P:(DE-He78)94ae391f53fb9285e1b68f9930615af1$$aSchulze, Almut$$b12$$udkfz
000179297 7001_ $$aDiefenbacher, Markus$$b13
000179297 7001_ $$00000-0001-7650-8458$$aRosenfeldt, Mathias T$$b14
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000179297 9141_ $$y2022
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