DS0403 - Exploration des systèmes et organes leur fonctionnement normal et pathologique : physiologie, physiopathologie, vieillissement

Connexin 43: a new mediator and target for chronic kidney disease – ConTarKiD

Submission summary

Chronic Kidney Disease (CKD) is a major burden of public health affecting millions of people around the world. Even though significant progress has been made and many aspects of the complex mechanisms orchestrating progression of renal disease have been identified, it still remains a fact that there is no specific treatment unequivocally shown to slow or arrest the worsening of CKD. Therefore, detection of the disease in very early stages and discovery of novel therapeutic targets are of crucial importance for an efficient treatment.

The general objective of the present proposal is to get insights into the role of Cx43 in the functional and structural adaptation of kidney in response to chronic aggressions of tubulointerstitial, glomerular or systemic-vascular origin, using novel tissue and time-conditional genetic models of mice.

The specific hypothesis behind this proposal, strongly supported by our preliminary studies, is that Cx43 can be de novo activated following aggression in the adult tissue to induce phenotypic changes promoting the adaptation of the aggressed tissue to the new pathological environment. Since these structural and functional alterations are an important part of the pathogenesis of the disease, we further hypothesize that Cx43 is a key factor to the progression of the disease and that inhibiting its activation will have beneficial effects.

Specific aims are to investigate:
1) If tissue and time specific Cx43 expression induces renal disease and inversely, if inhibition of its expression leads to tissue protection.
2) If we can apply therapeutic strategies that will block Cx43 overexpression or Cx43 gap junction channels function and preserve organ function.

To achieve these goals, we will take advantage of conditional transgenic mouse strains allowing Cx43 overexpression or deletion in a tissue and time-specific matter. Most of these strains have been recently generated, are viable and ready for immediate use. Our plan is to combine state of the art genetic, molecular, biochemical, histological techniques as well as ex vivo and in vivo functional approaches.

Originality-Novelty: This application builds upon the complementary expertise of the 2 teams: the laboratory of Christos E Chadjichristos has a recognized expertise in renal pathology and Nicolas Picard is a well known expert on renal physiology. The project emerged from results obtained during our fruitful collaboration when analyzing the role of different connexins (Cx37, 40 and 43) in normal renal function and kidney injury. The implementation of the objectives of the project relies on the use of cutting edge interdisciplinary technology, such as conditional transgenic strains, live recording of local hemodynamics and basic molecular and cellular biology techniques. Cx43 is considered as an important mediator of the progression of inflammatory diseases in various organs. However its implication in chronic kidney diseases is poorly known. Recent results obtained from the partners teams strongly suggest that Cx43 can be de novo induced and spread deleterious signals in epithelial or endothelial cells in adult animals during physiopathological conditions.


Relevance-Importance: Demonstration of a local involvement of Cx43 expression and/or function in the progression of renal disease will open a completely new field in our understanding of the physiopathological mechanisms affecting the function of these key organs. Thus, the outcome of our research will be wide, ranging from cellular biology in order to characterize the consequences of Cx43 channels impairment or activation, to preclinical studies looking for new markers of progression of renal failure and novel therapeutic targets of renal diseases.

Project coordination

Christos CHADJICHRISTOS (Institut National de la Santé et de la recherche Médicale-Délégation Régionale Paris 6)

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-DR Paris 6 Institut National de la Santé et de la recherche Médicale-Délégation Régionale Paris 6
INSERM - DR PARIS 6 Institut National de la Santé et de la Recherche Médicale - Délégation Régionale Paris 6
LBTI-CNRS Laboratoire de Biologie Tissulaire et Ingénierie Thérapeutique

Help of the ANR 499,369 euros
Beginning and duration of the scientific project: September 2015 - 48 Months

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