INTRA-CREATE COLLABORATION GRANT

Background

The goals of this proposal stem from the successful collaboration between Wong and Engelberg in the course of the MMID2 (Molecular Mechanisms of Inflammatory Diseases) SHARE- CREATE programme (2016-2021).

In MMID, a novel mouse model was established, in which it is possible to activate the enzyme p38 in a tightly controlled manner and a tissue-specific manner, temporally and spatially. It was found that induction of p38 activity per se in the liver, in the absence of triggers that had been so far considered critical, was sufficient to induce a fatty liver disease. This finding suggests a significant modification of current paradigms on the onset and aetiology of this incurable, chronic inflammatory diseases.  

Currently, no model exists in which fatty liver or respiratory diseases are induced solely by activation of a single protein by mutation or gene amplification, emphasising the uniqueness of the model we developed. This quality of the models, combined with the drawbacks of the currently available models, strengthen our confidence that we can provide novel conceptual and practical perspectives on inflammatory diseases. The fact that our models have been already established (in the NUS-HUJ MMID2 CREATE project), which strengthens our confidence even further.

Aims

The objectives of this study are therefore clear and straightforward, namely, to exploit the experimental models already established, in which we controllably induce liver inflammatory disease, for unravelling the molecular events that underlie the development and the exact kinetics of the malady.

Research plan and impact

As inflammatory diseases are so prevalent, affecting hundreds of million patients, and as no clear understanding of their aetiology is available, we expect that new models for these diseases will have a dramatic impact, by contributing to basic research in biomedicine. We foresee an important impact on the effort to treat inflammatory diseases because of the availability of reliable models that would facilitate the testing of already existing therapeutic strategies as well as the developing new ones. The concrete and immediate impact of the project would be mainly on liver diseases, and to some extent on lung diseases. Yet, the concept that this project delivers could be relevant to many diseases. The hope is that this grant will also have a serious impact on the industrial sector that will begin to use the new models .In this regard it should be pointed out that all models we are developing are based on technologies developed in our laboratories. Those include the engineered p38 molecules and the particular mode through which we express them in a spatially and temporally controlled (and even reversible) manner in mice.

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