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Role Of Retinoid Signalling In Striatal Development And Functions: Relevance For Understanding And Treatment Of Restless Legs Syndrome

Reference : PhD Wojciech KREZEL

Offer publication : April 5, 2016

Restless legs syndrome (RLS) is one of the most common neurodevelopmental disorders affecting up to 5-10% of population in Europe and North America. It is characterized by persistent discomfort and restlessness in the legs, with symptom severity increasing at night. This causes severe sleep disruption leading to significant secondary effects on physical, mental and social health. The cause of RLS is not well understood, and
available treatments such as dopaminergic agents are thus limited in efficacy, particularly for long-term disease management. Clinical data indicate that both genetic and environmental factors contribute to the etiology of the disease. The strongest known genetic risk factors for RLS are variants in the gene MEIS1. Our published and preliminary data indicate that the activity of MEIS1 affects the development of the striatum, an RLS-associated brain region, and such control may involve abnormal signalling through retinoid receptors.

The project will aim to identify the role of retinoid signalling and MEIS1 in the mechanisms underlying RLS. In the first part of the project, the PhD fellow will investigate development of striatum and dopaminergic signaling in genetic mice models with
compromised Meis1 and/or retinoid signaling. The follow-up pharmacological analyses and behavioral studies of such models will address functionality of dopaminergic signaling with respect to control of motor, affective and cognitive functions (RLS-related behaviors). Finally, a series of in vitro and in vivo studies will aim at identification of novel treatments for RLS therapy. In particular a series of novel compounds will be tested in primary neuronal
cultures from genetic animal models used in this project to identify a lead compound which will be next tested in vivo. Selected behavioral tests will be used to monitor efficiency of such treatments. Collectively, these studies are expected to characterize the developmental origin of RLS, provide significant insight into the mechanisms of RLS, and define novel targets for more effective therapeutic approaches.

- WISHED SKILLS : Motivation, team work, good organization skills, basic techniques of molecular and cellular biology.

- EXPERTISES WHICH WILL BE ACQUIRED DURING THE TRAINING : Carry out a research project, bibliography search, and participation in planning of experimental design, critical analyses of obtained data and their presentation, writing manuscripts. Strong expertise will be acquired in genetics and genomic analyses, histology (e.g. sample preparations, immunohistochemistry), cellular (e.g. primary cell cultures) and molecular biology techniques (qPCR, in situ hybridization), gene expression interference (miRNA, siRNA or CRISPR), and various optical imaging techniques.

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Application Deadline : Dec. 31, 2016

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