Studies on the effect of caveolin-analogues on the structure and function of caveolae

• Applicant: Dr. Jan Robert Krähling
• Subject Area: Pharmacology
• Term: from 2012 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 221948288

Endothelium-derived nitric oxide (NO) is a critical mediator of diverse functions in the cardiovascular system. During the last years a concept had developed that the eNOS activation/inactivation can be regulated by phosphorylation and locale specific protein-protein interactions with several proteins including caveolin-1 (Cav-1). In preliminary experiments, the interaction between eNOS and Cav-1 has been dissected from its inhibitory function using mutagenesis of the caveolin scaffolding domain (CSD) and a novel cell permeable, eNOS activator peptide was developed (Cav-1-F92A). Thus, the hypothesis arises that a mutant of Cav-1 that does not inhibit eNOS or a cell permeable eNOS activator will antagonize the inhibitory role of Cav-1 on eNOS and promote NO release and improve endothelial cell health and blood flow. To examine the regulation of this important interaction in more detail, the following specific aims are proposed: 1.) Reconstitute Cav-1-F92A into wild-type and Cav-1-knockout endothelial cells and vessels and 2.) generate transgenic mice that inducibly express Cav-1-F92A in the endothelium. Collectively, this work will facilitate the understanding of the molecular machinery required for eNOS regulation in EC. Scientific Relevance: This research is relevant to public health since endothelial dysfunction is a common manifestation of most cardiovascular diseases. Research supported by this grant may help identify new drugs that reduce heart disease and improve the quality of life of people suffering with cardiovascular disease.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. William C. Sessa