NOTCH3: A NEW MEDIATOR AND TARGET OF THERAPY FOR CHRONIC KIDNEY DISEASE – Active Notch

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 Notch3 in the functional and structural adaptation of kidney and vessels 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, which is strongly supported by our preliminary studies, is that Notch3 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 of are an important part of the pathogenesis of the disease, we further hypothesize that Notch3 signaling 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 specific tissue and time Notch3 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 Notch3 activation and preserve organ function.

To achieve these goals, we will take advantage of transgenic strains of mice conditionally over-expressing the intracellular domain of Notch3 (or lacking Notch3) in a tissue and time-specific matter. Most of these conditional strains of mice have been recently generated, are viable and ready for immediate use. Our plan is to combine state of the art genetic, molecular, biochemical, histological 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 Chatziantoniou has a recognized expertise in renal physiopathology, and Jane-Lise Samuel’s laboratory is a well known expert on cardiovascular physiopathology. The project emerged from results obtained during our fruitful collaboration regarding the role of Notch3 in the normal development and function of renal and cardiac vessels (2 original publications, 2 in 2nd revision, 2 in preparation). 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 of intravital microscopy in mice, and methods of molecular and cellular biology. Notch3 was classically considered as an important gene for the development of vessels in early life, with limited implication in the vessel function during adulthood. However this notion is challenged by the recently results from the partners teams strongly suggesting that Notch3 signaling can be induced or de novo activated in epithelial or smooth muscle cells in adult animals during physiopathological conditions.

Relevance-Importance: Demonstration of a local involvement of Notch-3 activity and/or signaling in the progression of renal and/or cardiac 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 to characterize the consequences of Notch3 pathway impairment or activation to clinical studies looking for new markers of progression of renal and heart failure and to discovering novel targets for therapy of these diseases.