1) Name – Title of the research project in CCHD
Christine Mannhalter: The birth of blood platelets, their interaction with leukocytes, and their role in thrombotic diseases
2) Coordinates of the Faculty Member
Department of Medical and Chemical Laboratory Diagnostics, Medical Univ. Vienna, Währinger Gürtel 18-20, A-1090 Vienna; Tel +43 1 40400-2085; Fax +43 1 40400-2097; email: christine.mannhalter@meduniwien.ac.at.
3) Keywords
Biochemistry, physiology and pathology of the haemostatic system including platelets
Identification of genetic risk factors and risk profiles of vascular diseases
Gene expression analyses
4) Research interest of the Faculty Member
Dr. Mannhalter and her team are interested in the identification of genetic risk factors of vascular diseases. In cooperation with national and international colleagues she built up a stroke and a venous thrombosis patient data base. Using different approaches several genetic variants were found to be associated with vascular diseases. Dr. Mannhalter is now focusing on the characterisation of the functional effects of different mutations. Certain variants of the genetically highly variable P-selectin, an important adhesion molecule mediating the binding between platelets and leukocytes, platelets and endothelial cells, and probably also between tumor cells and platelets, have been found to influence arterial and venous thrombosis. The group is currently working on the detailed characterization of P-selectin mutations and P-selectin haplotypes regarding the regulation of P-selectin synthesis eg by NFĸB or ets-1, P-selectin stability eg via an effect of the mutations on glycosylation, an impact on platelet reactivity, or platelet-leucocyte and platelet-endothelium interaction. In this context the fate of P-selectin variants and other platelet glycoproteins during differentiation of megakaryocytes from hematopoietic precursor cells is of special interest and will be studied in detail. Above that, the group is particularly interested to elucidate the role of cation channels and calcium influx in megakaryopoiesis and thrombopoiesis and has begun to study transient receptor potential cation channels (TRPC6, TRPC3) during megakaryocyte development.
5) Collaborations within CCHD
With O. Wagner exists a long standing collaboration with respect to genetic risk factors in vascular diseases which is extended in CCHD. Together with BR. Binder the interactions of genetically modified platelets with endothelial cells will be investigated. With E. Jensen-Jarolim we began to study the details of the interaction between megakaryocytes, platelets and IgE of patients with allergies. With the help of G. Supperty-Furga mass spectroscopy of P-selectin variants will be performed to define the glycosylation profiles of P-selectin variants. In cooperation with H. Lassmann electron and confocal microscopy of megakaryocytes as well as genetically modified megakaryocytes at different stages of differentiation will be carried out.
6) Collaborating research groups where PhD Students can perform their research stay
Dr. Peter J. Newman, Blood Research Institute, Blood Center of Wisconsin, Milwaukee, USA.
Dr. Andrew Weyrich, Department of Internal Medicine, University of Utah, Salt Lake City, UT 84112, USA.
Dr. Ulrich Walter, Institute of Clinical Biochemistry and Pathobiochemistry, University of Wuerzburg, Wuerzburg, 97080, Germany
7) Industrial partners (if applicable)
Dr. May Luke, Celera Research Laboratories, USA; Genetic risk factors in stroke
8) Know-how and infrastructure of the research group
This research group has extensive experience in the identification of genetic risk factors in common diseases (Lalouschek et al 2007, Ay et al 2008, Greisenegger et al 2008). Several years ago the group has started to work with platelets and megakaryocytic cells, cultivate and differentiate them and analyse the transcription of several glycoproteins in platelets (Rieger et al 2001, Stiegler et al. manuscript accepted for publication ). Within the CCHD we now began to develop suitable methods to differentiate megakaryocytes from hematopoietic stem cells obtained from cord blood. These cells will be used for transfection, RNAi treatment and for the analysis of the effect of various external factors such as oxidized lipoproteins on platelet signaling.
All members of the research group have access to a complete cell culture lab (microscopes, sterile hoods, incubators, fluorescence microscopes), to flow cytometry and a FACS sorting unit, a fully equipped molecular biology lab including a sequencing unit, a microarray unit, and a standard biochemistry lab.
