Glucose- and methylglyoxal-induced metabolic memory: Studies in C. elegans

• Applicant: Dr. Andrea Schlotterer
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 434144982

While numerous studies on retinae of STZ-diabetic mice and rats have identified basic mechanisms of metabolic memory, genome-wide gene expression studies for the identification of potential target genes of metabolic memory are rare. In particular, in the context of metabolic memory, the effects of changes in the transcriptome on neuronal functions have not been studied. On the other hand, the reduction of oxidative stress by the use of anti-oxidative substances offers the possibility to prevent the formation of metabolic memory.The aim of the proposed project is therefore, in addition to our previously established metabolic-memory model of microvascular damages of the mouse retina, to use C. elegans for development of a surrogate of functional neuronal damages, persisting as a result of metabolic memory in the neuronal part of the neurovascular unit of the diabetic retina.C. elegans will be used to study both the glucose- and methylglyoxal-induced metabolic memory. Mechanically, these two forms of metabolic memory differ in the profile of the oxidative stress level. While in glucose-induced metabolic memory the initially increased glucose flux leads in particular to methylglyoxal modifications of MRC components and ultimately permanently increased ROS formation, in methylglyoxal-induced metabolic memory AGE formation is less specific and may also induce neuronal damage via ROS-independent pathways.Based on this, C. elegans will be developed as a system for the screening of anti-oxidative substances to find new approaches to affect the pathogenesis of diabetic retinopathy by inhibiting metabolic memory.In the first part of these studies we plan to1a. to establish C. elegans as a model system for the study of glucose- and methylglyoxal-induced metabolic memory, and1b. to validate known metabolic memory target genes in C. elegans.The aims of the further parts of the project are2a. the identification of novel target genes of glucose and methylglyoxal-induced metabolic memory,2b. the identification of target genes of metabolic memory-induced neuronal damage,2c. the establishment of C. elegans as a system for the screening of anti-oxidative substances, and2d. the study of the influence of anti-oxidative substances on the formation of a metabolic memory in C. elegans.

• DFG Programme: Research Grants