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MD SP16

Hyperglycemia-evoked alterations in Ca2+ homeostasis and in Ca2+-dependent translational profiling in endothelial cells

Supervisor (Heidelberg): Marc Freichel
Co-Supervisor (Groningen): Robert Henning
Graduate: n.n.

Project description

Chronic hyperglycemia alters cellular Ca2+ homeostasis in various cells susceptible to diabetic longterm complications including endothelial cell and platelets. This is explained by modulation of the function, transcription and/or posttranslational modification of cation channels of the TRP and ORAI channel family and of regulator proteins thereof (1, 2, 3). In this project, we address the contribution of cation channels regulating alterations of Ca2+ homeostasis in endothelial and platelets evoked by reactive metabolites accumulating under chronic hyperglycaemia (4). Functional implications of altered cellular Ca2+ homeostasis for endothelium-mediated relaxation will be analysed in ex-vivo arterial sections. Genes that are differentially translated in the endothelium under chronic hyperglycemia in a Ca2+-dependent manner will be analysed using ribosomal profiling (4).

References

  1. Guerrero-Hernandez A, et al. Cell Calcium. 2014;56: 323–331.
  2. Arruda AP, et al. Cell Metabolism. 2015; 22: 381-397.
  3. Bogesky I, et al. Cell Calcium. 2011;50:407–423.
  4. Forbes JM and Cooper ME. Physiol Rev. 2013;93:137-88.
  5. Schumacher D, et al. Cancer Cell. 2013;24:130-7.
  6. Herroeder S, et al. Immunity. 2009;30:708-20.
  7. Camacho Londoño JE, et al. Eur Heart J. 2015; 36: 2257-66.
  8. Zhang W,et al. PLoS One. 2016;11(1):e0145513.
  9. Sudivakkam PC, et al. Mol Pharmacol. 2012; 81: 510-26.
  10. Freichel M, et al. Nat Cell Biol. 2001; 3: 121-7.
  11. Mazagova M, et al. Am J Physiol Renal Physiol. 2013; 305: F1249-64.
  12. Mazagova M, et al. Am J Physiol Heart Circ Physiol. 2013;304:H709-18.

Methods that will be used

Diabetic animal models, cultured endothelial cells, intracellular calcium imaging (FURA-2 fluorimetry), epifluorescent imaging of cardiac Langendorff preparations from mice expressing GCamp5G selectively in endothelial cells, expression analysis (qPCR, Western blot), in vitro vessel contractility (isometric and isobaric myography)

Collaboration Partners

  • Robert Henning & Dr. Leo Deelman, Groningen
  • Supervisors of GRK 1874 DIAMICOM in Mannheim, Heidelberg, and Groningen

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