TARKINAID project structure
To achieve project objectives TARKINAID project is organized in 7 Work Packages (WPs):
WP1: Chemical synthesis and structural optimization of kinase inhibitors
The objective of this work package is the generation and supply of various Src-family kinase inhibitors for further analysis, as well as the characterization of their effects on recombinant Src-family kinases. The inhibitors originate from three different sources:
a) known Src-family inhibitors that are in clinical use for oncology patients
b) novel Src-family inhibitors
c) novel Hck inhibitors
The above molecules and their new analogues are being synthesized, tested in cell-free Src-family kinase assays and supplied for other members of the consortium for inflammation studies and structural optimization.
WP2: Analysis of kinase inhibitors in in vitro inflammation and ADME-Tox assays
The objective of this work package is the analysis of already existing and newly developed kinase inhibitors in various in vitro assays such as inflammation-related functional responses of leukocytes and general ADME/Tox assays. The results of these assays are used to select and further optimize the Src-family inhibitors with the most beneficial anti-inflammatory action.
WP3: Initial screening for in vivo safety and efficacy
The objective of this work package is the initial analysis of the in vivo safety and efficacy of Src-family inhibitors selected in WP1-2. Safety experiments focus on in vivo toxicity and the effects of the inhibitors on the course of various infectious diseases. Initial efficacy assays include the analysis of the selected inhibitors on the Arthus reaction, acute lung inflammation as well as on in vivo migration of leukocytes. The results of these studies are being fed back to WP1 for further optimization of the inhibitor structures.
WP4: Analysis of kinase inhibitors in chronic in vivo inflammation models
The objective of this work package is the analysis of the effect of the most promising kinase inhibitors (selected in the in vitro and initial in vivo assays in WP1-3) in various in vivo assays of chronic autoimmune and inflammatory disease models in mice. The disease models include various autoimmune arthritis models, autoimmune skin and lung inflammation models, as well as an inflammation-induced lung fibrosis model. Some of those models are triggered by passive autoantibody injection whereas others are triggered by active immunization, pathogenic transgene expression or administration of foreign particles.
WP5: Gene knockout studies and target spectrum identification
The aim of this work package is to gain further insight into the effects of the selected inhibitors and Src family inhibitors in general in chronic autoimmune and inflammatory diseases. To this end, the consortium performs detailed analysis of the target spectrum of the selected kinase inhibitors and perform additional gene knockout experiments to obtain more detailed information on the role of Src-family kinases in the various assays to be used during the project. These studies run in parallel to the inhibitor studies described in WP2-4, use the same assays as in those WPs, and complement the results obtained in those pharmacological experiments.
WP6: Management, Review and Assessment
The aim of this work package is to guarantee full synergy and integration among TARKINAID beneficiaries to provide added international value and extend the state of the art in research on therapeutic treatment of inflammatory diseases. This facilitates the following outcomes:
- Maintenance of a defined time-schedule of the research
- Achievement of the planned objectives
- Immediate recognition of problems, their evaluation and the adoption of actions to solve them.
- Integrate and expand European and Brazilian state-of-the-art in research on identification of new therapeutic targets and innovative compounds for the clinical treatment of acute and chronic inflammatory diseases.
WP7: Dissemination and Diffusion of project results
The general objective of this work package is to disseminate results as well as general awareness of issues addressed by the TARKINAID project. To this principle dissemination plans are carefully designed in order to guarantee an effective communication of TARKINAID results to the scientific community as well as among TARKINAID beneficiaries. Particular attention is devoted to train scientists from Brazil belonging both to the TARKINAID Consortium as well as to other Brazilian organizations in order to improve their collaboration with research groups in Europe.
Main relationship between TARKINAID WPs: