Journal
CELL METABOLISM
Volume 22, Issue 2, Pages 239-252Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2015.07.015
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Funding
- NIH [RO1 DK67536, RO1 103215, UC4 DK104167-01, DP2OD006668, DP3 DK094333-01, JDRF 17-2013-310, K99DK090210, R00DK090210, 3-APF-2014-182-A-N, JDRF 10-2012-240, P41 GM103493]
- Mary K. Iacocca Foundation
- DOE/BER and located at Pacific Northwest National Laboratory
- DOE [DE-AC05-76RL0 1830]
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The mechanisms underlying the development of complications in type 1 diabetes (T1D) are poorly understood. Disease modeling of induced pluripotent stem cells (iPSCs) from patients with longstanding T1D(disease duration >= 50 years) with severe (Medalist +C) or absent to mild complications (Medalist -C) revealed impaired growth, reprogramming, and differentiation in Medalist +C. Genomics and proteomics analyses suggested differential regulation of DNA damage checkpoint proteins favoring protection from cellular apoptosis in Medalist -C. In silico analyses showed altered expression patterns of DNA damage checkpoint factors among the Medalist groups to be targets of miR200, whose expression was significantly elevated in Medalist +C serum. Notably, neurons differentiated from Medalist +C iPSCs exhibited enhanced susceptibility to genotoxic stress that wors-ened upon miR200 overexpression. Furthermore, knockdown of miR200 in Medalist +C fibroblasts and iPSCs rescued checkpoint protein expression and reduced DNA damage. We propose miR200-regulated DNA damage checkpoint pathway as a potential therapeutic target for treating complications of diabetes.
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