The role of protein tyrosine phosphatases for the regulation of integrin activity and leukocyte recruitment.

• Applicant: Professor Dr. Alexander Zarbock
• Subject Area: Anaesthesiology
• Term: from 2013 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 245856170

Leukocyte recruitment into inflamed tissue proceeds in a cascade-like fashion. The first contact of neutrophils with the endothelium is mediated by selectins and their counter-receptors, followed by rolling and integrin-mediated arrest. While rolling, neutrophils collect different inflammatory signals which can activate several pathways leading to integrin activation, leukocyte adhesion to endothelium, and transmigration into inflamed tissue. In order to limit inflammation and immune function, signaling pathways must be turned off. Mice lacking negative regulators often have a pro-inflammatory phenotype. Leukocytes express different protein tyrosine phosphatases (PTPs), which are involved in regulating the activity of different signaling pathways. Furthermore, signaling pathways can also be deactivated by cell surface receptors that contain immunoreceptor tyrosine-based inhibitory motifs (ITIMs). However the role of negative regulators for the different steps of leukocyte recruitment is still unknown. Therefore, the aim of the proposal is to identify how these negative regulators may affect integrin activity and the different steps of leukocyte recruitment by using gene-deficient mice, retrovirus technology, and biochemical methods. Further understanding of the role of negative regulators in leukocyte recruitment and activation is necessary in order to therapeutically target specific molecules and inhibit specific functions of leukocytes without affecting others.

• DFG Programme: Research Grants