Inhibition of Epithelial to Mesenchymal Transition (EMT) for treatment of Kidney Fibrosis (Expansion of project number 2016-8675)
No update is needed. Kidney fibrosis is the pathohistological correlate of chronic kidney disease (CKD), which is common, often unavoidable, irreversible and can eventually lead to end-stage renal disease. We still do not have effective therapy for kidney fibrosis although it is a common consequence in patients with diabetes and/or hypertension. EMT is a process by which epithelial cells change into cells with mesenchymal characteristics leading to the accumulation of extracellular matrix (fibrosis). EMT plays important role in the development of kidney fibrosis. Axl is a central pathway/receptor involved in EMT.
The aim of this project is to explore the effect of four Axl signalling inhibitors (three small molecules and one antibody) in combination with standard therapeutic agents being used in the clinic on the development of kidney fibrosis.
We hypothesize that treatment with Axl inhibitor in combination with conventional therapy reverses the development of kidney fibrosis in mice. This project will help to elucidate both the impact of EMT and Axl in kidney fibrosis but also analyze the potential of treatment with Axl-inhibitors in this disease. It is our intension to plan a clinical study as a consequence of our results in these experiments.
We hereby apply for the use of a total number of 960 mice in this project over the course of 3 years.
Repalcement, Reduction and Refinement
-We already analyzed available tissues from the Norwegian Kidney biopsy registry as well as from previous animal experiments and archives to analyze the expression of EMT markers such as Axl (manuscript under preparation). This analysis revealed a higher expression levels of EMT markers in this cohort (including some members of the Axl-pathway that are targeted by the proposed inhibitors).
-Previously performed in vivo studies (FOTS 8218 and 5984) and even clinical trials presently ongoing involving Axl inhibitors have have shown effective EMT inhibition in other diseases. An extensive amount of in vitro and in vivo studies has been performed to validate the toxicity and side effects of the Axl inhibitors to be investigated in this project.
- kidney fibrosis is a disease that develops as a consequence of multiple systemic diseases such as hypertension and diabetes. It is not possible to generate a kidney fibrosis model in vitro as several compartments of the kidney are affected and the disease interacts with the systemic impact of e.g. hypertension or diabetes. Therefore, cell culture studies cannot replace the complexity of a mouse model in response to drug treatment.
- A maximum number of animals/experimental group will be limited to 10 including animals that will be sacrificed for mechanistic studies before the end point. Several experimental groups will be included in one experiment to minimize the number of control animals to be used. The personnel performing these experiments, and accordingly responsible for the well being of the animals is experienced in the proposed models.
The aim of this project is to explore the effect of four Axl signalling inhibitors (three small molecules and one antibody) in combination with standard therapeutic agents being used in the clinic on the development of kidney fibrosis.
We hypothesize that treatment with Axl inhibitor in combination with conventional therapy reverses the development of kidney fibrosis in mice. This project will help to elucidate both the impact of EMT and Axl in kidney fibrosis but also analyze the potential of treatment with Axl-inhibitors in this disease. It is our intension to plan a clinical study as a consequence of our results in these experiments.
We hereby apply for the use of a total number of 960 mice in this project over the course of 3 years.
Repalcement, Reduction and Refinement
-We already analyzed available tissues from the Norwegian Kidney biopsy registry as well as from previous animal experiments and archives to analyze the expression of EMT markers such as Axl (manuscript under preparation). This analysis revealed a higher expression levels of EMT markers in this cohort (including some members of the Axl-pathway that are targeted by the proposed inhibitors).
-Previously performed in vivo studies (FOTS 8218 and 5984) and even clinical trials presently ongoing involving Axl inhibitors have have shown effective EMT inhibition in other diseases. An extensive amount of in vitro and in vivo studies has been performed to validate the toxicity and side effects of the Axl inhibitors to be investigated in this project.
- kidney fibrosis is a disease that develops as a consequence of multiple systemic diseases such as hypertension and diabetes. It is not possible to generate a kidney fibrosis model in vitro as several compartments of the kidney are affected and the disease interacts with the systemic impact of e.g. hypertension or diabetes. Therefore, cell culture studies cannot replace the complexity of a mouse model in response to drug treatment.
- A maximum number of animals/experimental group will be limited to 10 including animals that will be sacrificed for mechanistic studies before the end point. Several experimental groups will be included in one experiment to minimize the number of control animals to be used. The personnel performing these experiments, and accordingly responsible for the well being of the animals is experienced in the proposed models.