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Valdez, Ivan

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Valdez

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Valdez, Ivan

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    Preserved DNA Damage Checkpoint Pathway Protects against Complications in Long-Standing Type 1 Diabetes
    (Cell Press, 2015-08-04) Bhatt, Schweta; Gupta, Manoj; Khamaisi, Mogher; Martinez, Rachael; Gritsenko, MA; Wagner, Bridget K.; Guye, Patrick; Busskamp, Volker; Shirakawa, Jun; Wu, Gongxiong; Liew, CW; Clauss, Therese; Valdez, Ivan; El Ouaamari, Abdelfattah; Dirice, Ercument; Takatani, Tomozumi; Keenan, Hillary A.; Smith, RD; Church, George; Weiss, Ron; Wagers, Amy; Qian, Wei-Jun; King, George; Kulkarni, Rohit
    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 worsened 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.