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Projekt
Regulation of pericytes by Angiopoietin2-studies in new animal models
Antragsteller
Professor Dr. Hans-Peter Hammes
Fachliche Zuordnung
Pathologie
Förderung
Förderung von 2001 bis 2006
Projektkennung
Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 5347244
Retinopathy is the most prevalent microvascular complication in diabetes. The earliest indication of hyperglycemia-induced retinal capillary damage is the loss of pericytes. Pericyte recruitment as an important part of vessel maturation involves several ligand-receptor systems including the Angiopoietin-Tie system. Tie2 mediates the dual effects of its two ligands angiopoietin 1 and 2, in which angiopoietin 1 (Ang 1) activates Tie2 while angiopoietin 2 (Ang 2) appears to be a natural antagonist of angiopoietin-1. For a better understanding and a possible basis for future interventions, we propose to establish and characterize a transgenic mouse which overexpresses Ang 2 under control of the photoreceptor opsin promoter in which pericyte recruitment, retinal capillary remodelling, and vascular regression is studied during postnatal development, in diabetes, and during hypoxia-induced proliferative retinopathy. This transgenic mouse line will be crossbred to a transgenic line which expresses the reporter gene LacZ under a pericytespecific promoter. This model enables to study pericyte modulation by Ang 2. Using a third transgenic mouse which expresses LacZ under the Ang 2 promoter, we will study the functional role of Ang2 in early diabetic pericyte loss. Ang 2 expression is modifiable by a variety of approaches, including Angiotensin receptor inhibition, inhibition of HB-EGF activation, EGF-receptor modulation and by reactive oxygen species. These targets of Ang 2 modifiers will be tested in in vivo models using Ang 2 species. These targets of Ang 2 modifiers will be tested in in vivo models using Ang 2 expression and pericyte recruitment in early diabetes as markers. In summery, we will combine retinal analysis in development, and in diabetic and proliferative retinopathy with new transgenic mouse models whose common denominator is the modulation of Ang 2.
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