Isothermal titration calorimetry (ITC) is a powerful biophysical method to study intermolecular interaction that has become widely used due to its technological advances. It enables the determination of all thermodynamical parameters of interaction after a single one-hour experiment. The key step of experimental data analysis is the fitting of obtained data using an appropriate binding model. Unfortunately, the limited set of models offered by manufacturers does not allow the full use of ITC for the study of complex molecular mechanisms of interaction. Recently we faced this problem when trying to investigate tau-tubulin binding. Because of its implication in cancer and neurodegenerative diseases this interaction presents great interest for both European host (CRO2) and my lab. Here I propose to create an advanced ITC data analysis tool that will allow researchers to create and share new binding models, so that any ITC end user can upload their experimental data and fit it using available models. This tool will also offer ITC data management and collaborative facilities. It should become a professional social network for ITC end users in Europe and beyond.
Using this tool, in the host institution, I will first focus on deciphering the exact mechanism of tau-tubulin interaction which, despite extensive study, remains unknown. I will then study the interplay between tau and anticancer drugs. This will allow us to evaluate the impact of anti-tubulin drugs used in cancer treatment on tau mechanism of action. During the return phase I will study the influence of two key factors implicated in neurodegenerative disorders, oxidative stress and zinc ions, on tau-tubulin interaction.
My experience in ITC and multidisciplinary skills combined with the expertise and resources of the host lab will ensure the success of this project. Moreover, new software tool will be made available to other European laboratories, helping establishing CRO2 as one of the leaders in ITC field.
Fields of science
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