Investigation of ligand-mediated regulation of the ITIM-containing receptor G6b-B

• Applicant: Dr. Timo Vögtle
• Subject Area: Cell Biology ; Hematology, Oncology
• Term: from 2015 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 273587674

Upon vascular injury platelets rapidly adhere to components of the newly exposed extracellular matrix (ECM), become activated and form a plug that seals the wound. However, excessive platelet activation may also occlude vessels, thereby causing life-threatening diseases like myocardial infarction or ischemic stroke. Platelets are derived from precursor cells in the bone marrow, termed megakaryocytes (MKs). A key question is how MKs, despite expressing the same repertoire of cell-surface receptors as platelets remain relatively refractory in the ECM-rich environment of the bone marrow. Recent studies in knockout-mice established the immunoreceptor tyrosine-based inhibition motif (ITIM)-containing receptor G6b-B as an essential inhibitory receptor in the regulation of MK function and platelet production, since its loss results in severe macrothrombocytopenia and aberrant platelet function. Despite this central role of G6b-B little is known about its regulation. The primary aim of the current project is to address two key questions regarding G6b-B: (i) the identification of its physiological ligand and (ii) the investigation of the biological functions of the G6b splice isoforms. These aims are not mutually exclusive; since G6b-A and -E have the same ectodomain as G6b-B, they must bind the same ligand, and potentially regulate G6b-B signaling by co-clustering or acting as decoy receptors, respectively. To address these questions a wide range of biochemical and molecular biological techniques as well as in vitro cell culture systems and mouse models will be used. Findings from this research project will contribute to our fundamental understanding of how platelet production and reactivity are controlled, and lay the foundation for development of novel anti-thrombotic drugs targeting this receptor.

• DFG Programme: Research Fellowships
• International Connection: United Kingdom
• Host: Professor Yotis Senis, Ph.D.