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Inhalt
Association of the CD40 gene rs1883832 C/T polymorphism with hyperglycemia-induced diabetic micro- and macroangiopathy
Supervisor (Heidelberg):Markus Hecker
Co-Supervisor (Groningen): Robert H. Henning
Graduate Pooja Joshi
Project Description
In this project we will investigate (i) whether the CD40 SNP imparts a pro-inflammatory phenotype to endothelial cells and smooth muscle cells through enhanced CD40 protein abundance and signalling under hyperglycaemic conditions, and (ii) if the C-allele of the T-1C SNP of the CD40 gene occurs more frequently in people with diabetes than healthy controls or other cardiovascular complications. In addition, we will investigate (iii) the pathophysiologic relevance of CD40 in dysfunctional coronary arteries, arterioles and capillaries in the hearts of Ins2Akita mice (which develop insulin-dependent diabetes, including hyperglycemia) and db/db mice (type 2 diabetes model) in comparison to Ins2Akita CD40-/- and db/db CD40-/- double knockout mice as well as wildtype litter mates. Finally, we will explore (iv) the notion that CD40-CD40L interactions play a role in the early phase of ferroptosis, a novel process of programmed cell death, directly affecting the heart by contributing to the development of endothelial dysfunction and (chronic) inflammation.
References
- *Wagner et al. Arterioscler Thromb Vasc Biol 2004;24:715-20
- *Wagner et al. Arterioscler Thromb Vasc Biol. 2009;29:1894-901
- *Wagner et al. Blood 2011;118:3734-42
- *Möller et al. Thromb Haemost 2015; 113:1095-108.
- Yun et al. PLoS One. 2014;9:e97289.
- *Popa et al. Proc Natl Acad Sci USA 2018;115:E5556-E5565.
* Own publications
Methods used
Cultivation of human ECs and SMCs, Western blot, qPCR, analysis of mouse models of diabetes and genetically modified mice, mass spectrometry imaging analysis
Collaboration Partners
- Stefan Kopf, Heidelberg
- Hans-Peter Hammes, Mannheim
- Bernhard Spengler, Gießen