DS0403 -

The divergent role of EGF and TGFa in chronic kidney disease: towards new therapeutic targets – GiF-KID

Submission summary


Chronic kidney disease (CKD), a major socioeconomic worldwide public health burden, is characterized by a progressive decline in renal function to end stage renal disease that can occur irrespective of the cause of the renal damage once a critical number of nephrons has been lost. Understanding the physiopathology of CKD progression is therefore a prerequisite for the development of efficient preventive strategies.

We have significantly contributed to the elucidation of the molecular mechanisms involved in CKD progression. By combining an experimental model of nephron reduction (Nx) with genomic and molecular approaches, we identified in EGFR (EGF receptor) the critical player of CKD as well as one of the most promising therapeutic targets of CKD progression. However, its chronic pharmacological inhibition cannot be proposed because of the severe adverse side effects. EGFR is activated by a multitude of ligands whose biological relevance has not been completely elucidated. The nature of the ligand may elicit distinct cellular responses. Our data suggest that, among these ligands, TGF-a and EGF seems to play major antinomic/divergent roles in CKD progression. More importantly, we confirmed that these results are relevant to humans since the increase of TGF-a and the decrease of EGF predict CKD progression in CKD patients.

Our working hypothesis is that the duality of nature of the ligand (TGF-a vs EGF) determines the fate of kidney towards compensation or deterioration after an initial injury. These two ligands might induce specific EGFR posttranslational modifications that might feed into ligand-specific distinct genetic networks.

The aim of this project is decipher the molecular mechanisms that accounts for the divergent role of EGF and TGF-a and to identify crucial specific modulators. We will combine in vivo and in vitro models, candidate and unbiased approaches with high throughput pharmacological screening. In particular, we will:

• characterize the cellular events triggered by EGF and TGF-a in renal epithelial cells. We will first determine the impact of Egf and Tgfa inactivation in different CKD mouse models. Then, we will focus on the cellular events known to participate to CKD progression: cell proliferation, cell polarity partial epithelial-mesenchymal transition (EMT).

• identify the genetic networks that account for the divergent role of EGF and TGF-a. We will characterize the differential expression of transcriptome in Egf-/- and Tgfa-/- mice after Nx. Then, we will map the chromatin changes that are responsible for these transcriptional effects.

• determine the ligand-specific receptor modifications and interactions in kidney of mice injected with the two ligands, using mass spectrometry. To study the spatial and temporal networks of EGFR partners, we will use an in vitro BioID screening. Candidates will be then validated in cell culture and in Egf-/- and Tgfa-/- CKD mouse models. In parallel, we will try to understand the mechanisms by which Lcn2 regulates EGFR trafficking.

• screen chemical libraries for drugs susceptible to selectively impact on EGF or TGF-a signaling. Biosensors able to predict TGF-a and EGF function will be used to “sense” the pharmacological effects. The most appropriate candidates will be finally validated in Nx mice.

This research project is based on a multidisciplinary approach that involves cell biology, genetics transcriptomics, proteomics and pharmacological screening to improve our knowledge of the complex pathogeneses of CKD progression. The results of this research proposal should provide a novel knowledge on EGFR and the signalling pathways that control CKD progression and, by consequent, to the design of more appropriate therapeutic strategies.

Project coordination

Fabiola TERZI (Institut National de la Santé et de la Recherche Médicale)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

INSERM Institut National de la Santé et de la Recherche Médicale
INSERM Institut National de la Santé et de la Recherche Médicale

Help of the ANR 515,400 euros
Beginning and duration of the scientific project: December 2016 - 36 Months

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