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

葡萄糖是修复机制的能量来源；然而，葡萄糖浓度升高会对细胞功能产生有害影响。研究了葡萄糖衍生的反应性代谢产物(甲基乙二醛和活性氧)对线虫神经元损伤的影响。研究表明，高糖诱导AICAR-甲酰转移酶/IMP-环水解酶(ATIC)，这是一种处理嘌呤中间体5-氨基咪唑-4-甲酰胺核糖核苷酸(AICAR)的酶。AICAR水平的增加激活了AMP依赖的激酶，导致反应性代谢物减少，减少了神经元损伤，最终延长了寿命。因此，这一保护途径被ATIC的激活和随后AICAR的减少所抑制。在线虫、转基因小鼠和患者的样本中，将研究葡萄糖如何诱导糖尿病的ATIC在维持细胞保护途径的同时维持RNA和DNA的合成。在我们以前工作的基础上，需要回答以下问题：a)AICAR及其在AMPK介导的糖尿病保护中的作用1。ATIC调节和AICAR浓度在糖尿病中是如何联系的？2.在糖尿病中ATIC诱导的AMPK活性在调节ROS和反应性二羰基方面起什么作用？3.糖尿病患者ATIC和AMPK是否被ROS或甲基乙醛翻译后修饰，这是否影响它们的底物特异性和活性？4.ATIC对小鼠糖尿病晚期并发症有何影响？2)ATIC在糖尿病细胞修复机制中的重要性1。糖尿病引起的ATIC依赖的嘌呤合成在体内DNA修复中的作用是什么？2.抑制嘌呤合成在细胞修复和防止DNA双链断裂方面的后果是什么？通过了解糖尿病中AMPK激活和嘌呤合成之间的失衡平衡，将揭示有助于保护糖尿病引起的细胞功能障碍的新途径。

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.