Investigation of the roles of Tropomyosin 1 and 4 in haematopoiesis, megakaryopoiesis and platelet function

• Applicant: Dr. Irina Pleines
• Subject Area: Hematology, Oncology
• Term: from 2013 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 234458846

Platelet activation is essential for haemostasis, but can also cause life threatening diseases, such as heart attack or stroke. Recent studies demonstrate that platelet count (PLT) and platelet size (MPV) are independent risk factors for these diseases. Therefore, large genome-wide association studies (GWAS) of normal healthy individuals have been undertaken in order to detect the common genetic variants (single-nucleotide polymorphisms (SNPs)) associated with PLT and MPV. A recent comprehensive GWAS meta-analysis in the group of Prof. Willem H Ouwehand (Cambridge, UK) identified SNPs in two loci, Tropomyosin 1 and Tropomyosin 4, to be associated with these traits. Strikingly, a mouse mutagenesis screen in the host laboratory using PLT and MPV as parameters recently identified a pedigree with a mutation in the Tropomyosin 4 gene. Importantly, these mutant mice have a phenotype consistent with the one associated with SNPs in the human Tropomyosin 4 gene. The objective of this project is to elucidate for the first time the roles of Tropomyosin 1 and 4 in haematopoiesis, as well as platelet production and function using mouse models of Tropomyosin 1/4 dysfunction. Notably, the project will be carried out in close collaboration with Profs. Willem H Ouwehand and Peter Gunning (Sydney, AUS), a long-standing tropomyosin expert. This provides the unique opportunity to combine data obtained by detailed biological analysis of mouse models within this project with studies involving cutting edge human genetics. In summary, this approach will enable novel important insights into the roles of Tropomyosin 1 and 4 for haematopoiesis, megakaryopoiesis and platelet function with potentially significant clinical impact.

• DFG Programme: Research Fellowships
• International Connection: Australia
• Host: Dr. Benjamin Kile