Importance of ATIC at the interface between glucose-induced cellular injury and repair mechanisms

• Applicant: Professor Dr. Peter Nawroth
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: from 2011 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 193164225

Glucose serves as an energy source for repair mechanisms; however, elevated glucose concentrations have deleterious effects on cellular function. The effect of glucose derived reactive metabolites (methylglyoxal and reactive oxygen species) on neuronal damage has been studied in the nematode C. elegans. It has been shown that high glucose concentrations induce AICAR-formyl-transferase/IMP-cyclohydrolase (ATIC), an enzyme which processes the purine intermediate 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR). Increased levels of AICAR activate AMP-dependent kinase leading to a reduction in reactive metabolites, decreased neuronal damage and ultimately a prolonged lifespan. This protective pathway is, therefore, inhibited by activation of ATIC and the subsequent reduction in AICAR.In C. elegans, transgenic mice and patients' samples it will be investigated how glucose induced ATIC-induction in diabetes mellitus sustains both RNA and DNA-synthesis whilst maintaining cellular protection-pathways. Based on our previous work the following questions shall be answered:A) AICAR and its role in AMPK-mediated protection in diabetes1. How is ATIC regulation and AICAR concentration linked in diabetes?2. Which is the role of ATIC-induced AMPK activity in diabetes in respect to the regulation of ROS and reactive dicarbonyls, such as methylglyoxal?3. Is ATIC and AMPK post-translationally modified by either ROS or methylglyoxal in diabetes and does this affect their substrate specificity and activity?4. Which late diabetic complications are influenced by ATIC in mice? B) Importance of ATIC on cellular repair mechanisms in diabetes1. What is the role of diabetes induced ATIC dependent purine synthesis in DNA repair in vivo? 2. What is the consequence of an inhibition of purine synthesis with respect to cellular repair and protection against DNA double strand breaks?By understanding the disturbed balance between AMPK activation and purine synthesis in diabetes, new pathways shall be revealed that contribute to protection against diabetes induced cellular dysfunction.

• DFG Programme: Research Grants
• Participating Person: Dr. Michael Mendler