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，葡萄糖浓度升高对细胞功能有有害影响。研究了葡萄糖衍生的活性代谢物（甲基乙二醛和活性氧）对线虫神经元损伤的影响。研究表明，高葡萄糖浓度可诱导AICAR-甲酰基转移酶/ imp -环水解酶（ATIC），这是一种处理嘌呤中间体5-氨基咪唑-4-羧基酰胺核糖核苷酸（AICAR）的酶。升高的AICAR水平激活amp依赖性激酶，导致反应性代谢物减少，神经元损伤减少，最终延长寿命。因此，这种保护途径被ATIC的激活和随后的AICAR的减少所抑制。在秀丽隐杆线虫、转基因小鼠和患者样本中，研究葡萄糖诱导的糖尿病患者的atic诱导如何在维持细胞保护通路的同时维持RNA和dna的合成。基于我们之前的工作，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。糖尿病患者的ATIC调节和AICAR浓度是如何关联的？atic诱导的AMPK活性在糖尿病中对ROS和活性二羰基（如甲基乙二醛）的调节作用是什么？糖尿病患者的ATIC和AMPK是否被ROS或甲基乙二醛翻译后修饰，这是否会影响它们的底物特异性和活性？ATIC对小鼠糖尿病晚期并发症有哪些影响？B) ATIC在糖尿病细胞修复机制中的重要性。糖尿病诱导的ATIC依赖性嘌呤合成在体内DNA修复中的作用是什么？2. 嘌呤合成的抑制对细胞修复和保护DNA双链断裂有什么影响？通过了解糖尿病中AMPK激活和嘌呤合成之间的失衡，我们将发现新的途径，有助于防止糖尿病诱导的细胞功能障碍。

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.