Document Detail


Self-sufficient control of urate homeostasis in mice by a synthetic circuit.
MedLine Citation:
PMID:  20351688     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Synthetic biology has shown that the metabolic behavior of mammalian cells can be altered by genetic devices such as epigenetic and hysteretic switches, timers and oscillators, biocomputers, hormone systems and heterologous metabolic shunts. To explore the potential of such devices for therapeutic strategies, we designed a synthetic mammalian circuit to maintain uric acid homeostasis in the bloodstream, disturbance of which is associated with tumor lysis syndrome and gout. This synthetic device consists of a modified Deinococcus radiodurans-derived protein that senses uric acids levels and triggers dose-dependent derepression of a secretion-engineered Aspergillus flavus urate oxidase that eliminates uric acid. In urate oxidase-deficient mice, which develop acute hyperuricemia, the synthetic circuit decreased blood urate concentration to stable sub-pathologic levels in a dose-dependent manner and reduced uric acid crystal deposits in the kidney. Synthetic gene-network devices providing self-sufficient control of pathologic metabolites represent molecular prostheses, which may foster advances in future gene- and cell-based therapies.
Authors:
Christian Kemmer; Marc Gitzinger; Marie Daoud-El Baba; Valentin Djonov; Jörg Stelling; Martin Fussenegger
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Publication Detail:
Type:  Letter; Research Support, Non-U.S. Gov't     Date:  2010-03-28
Journal Detail:
Title:  Nature biotechnology     Volume:  28     ISSN:  1546-1696     ISO Abbreviation:  Nat. Biotechnol.     Publication Date:  2010 Apr 
Date Detail:
Created Date:  2010-04-09     Completed Date:  2010-05-19     Revised Date:  2011-01-26    
Medline Journal Info:
Nlm Unique ID:  9604648     Medline TA:  Nat Biotechnol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  355-60     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Biomimetics / methods*
Homeostasis / physiology*
Mice
Mice, Transgenic / metabolism*
Signal Transduction / physiology*
Uric Acid / metabolism*
Chemical
Reg. No./Substance:
69-93-2/Uric Acid
Comments/Corrections
Comment In:
Nat Biotechnol. 2011 Jan;29(1):22; discussion 22-3   [PMID:  21221092 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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