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Project

Manipulating Wnk kinase function as a therapeutic application in neurological diseases

Wnk is an essential kinase, found to be misregulated in different diseases such as hypertension, cancers and neuropathies. However, Wnk has only been extensively studied in renal tissue, where it regulates chloride homeostasis, and not much is known of Wnk function in other tissues. We recently discovered that loss of Wnk kinase in Drosophila sensory neurons results in axonal branching defects and axon degeneration. Loss of Wnk in cortical neurons of mice showed a similar phenotype. These results suggest a conserved function of Wnk in axon maintenance. We hypothesize that in the nervous system a novel effector pathway is the main target of Wnk function. The aim of this project is, therefore, to unravel this pathway with focus on the possibilities for therapy and is divided in 3 parts, namely (i) investigating the function of Wnk in axon maintenance (ii) unraveling this novel effector pathway and (iii) translation to vertebrate and disease model.

In the first part we will make a time course of the axon degeneration, also necessary for the upcoming rescue experiments, and study how and when defects in Wnk results in axon degeneration. Next to this axon degeneration, we will study whether Wnk is involved in the regulation of the presentation/trafficking of surface receptors such as Dscam and Robo1/2, since these receptors are known to be involved in axon branching. In the second part, a dual phosphoproteomics approach, followed by biochemical analyses, will be used for discovering novel effectors of Wnk. Since Wnk is a large protein (250kDa), the catalytic function will not be the only function of Wnk. These other functions can be revealed with an intragenic modifier screen. The last part will be done in a vertebrate nervous system, namely Xenopus tropicalis. We want to confirm the results obtained in Drosophila, as proof of the conserved functions of Wnk. However, the main goal of this last part is to test whether manipulation of Wnk can rescue or prevent axon degeneration. This will be done with a chemical-genetic approach to sensitize Wnk kinase for reversible inhibition. If rescue of axon degeneration is possible, this indicates the possibility of targeting Wnk as a therapy for neurodegenerative diseases.

To conclude, this project will lead to a better understanding of Wnk kinase function. This will open the possibility of studying Wnk as an important drug target for therapies of developmental or neurodegenerative diseases, or various cancers.

Date:15 Sep 2016 →  1 Jan 2017
Keywords:Neurology, Axon degeneration, Wnk kinase
Disciplines:Neurosciences, Biological and physiological psychology, Cognitive science and intelligent systems, Developmental psychology and ageing
Project type:PhD project