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Inhalt

MD SP05

Hyperglycemic memory–mechanisms relevant to the diabetic retina

Supervisor (Mannheim): Hans-Peter Hammes
Co-Supervisor (Groningen): Grietje Molema
Graduate: Malenka Zimmermann

Project description

Clinical and experimental evidence suggests that hyperglycemic memory is part of the complex pathogenesis of diabetic retinopathy. Perpetuation of oxidative stress, irreversible accumulation of advanced glycation end products (AGEs) and hyperglycemia-induced epigenetic changes are possible underlying mechanisms. However, given the unsolved question which pathogenetic mechanisms prevail at retinopathy onset, the gap needs to be closed between cellular memory experiments which reflects days, and animal experiments and human disease which represent years. The aim of the current project is to determine a. the clusters of retinal genes involved in hyperglycemic memory using state-of-the-art array technologies, b. the cellular compartments in which these genes are regulated and c. the underlying pathogenetic concept by comparing gene expressions patterns during euglycemic reentry versus metabolic signal blockade.

References

  1. Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res. 2010; 107: 1058-70
  2. Hammes HP, Du X, Edelstein D, et al. Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nat Med 2003; 9: 294-299
  3. Yao D, Taguchi T, Matsumura T, et al. High glucose increases angiopoietin-2 transcription in microvascular endothelial cells through methylglyoxal modification of mSin3A. J Biol Chem 2007; 282: 31038-45
  4. El-Osta A, Brasacchio D, Yao D et al. Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia. J Exp Med 2008; 205:2409-17
  5. Wang Q, Gorbey S, Pfister F, et al. Long-term treatment with suberythropoietic Epo is vaso- and neuroprotective in experimental diabetic retinopathy. Cell Physiol Biochem 2011; 27:769-82
  6. Zhong Q, Kowluru RA. Epigenetic changes in mitochondrial superoxide dismutase in the retina and the development of diabetic retinopathy. Diabetes. 2011; 60:1304-13

Methods used

Spontaneous and induced animal models of diabetes; Affymetrix Gene Array analysis; Illumina arrays; quantitative retinal morphometry, immunofluorescence and laser scanning microscopy, mass spectrometry, immunoblotting techniques

Collaboration Partners

  • Grietje Molema, Groningen
  • Supervisors of GRK 1874 DIAMICOM in Mannheim, Heidelberg, and Groningen

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