Reference : PhD Agnès Bloch Zupan
Signals guiding craniofacial development are also used in establishing sensory, motor, and cognitive function. Such widespread cranio-oro-facial phenotypes are often due to alterations in key DNA transcriptional factors or members of the DNA repair process. Our laboratory combines patient-based clinical screens with the strength of the IGBMC/Institute Clinique de la Souris (ICS) in creating and analyzing equivalent mouse models. We identify, treat, and perform genomic screenings of patients with unusual dental craniofacial defects (see http://www.eucor-uni.org/fr/2016/06/03/rarenet-defie-les-maladies-rares-dans-la-vallee-du-rhin-superieur) to identify candidate genes.
Currently, we are investigating a novel leucine zipper domain-containing protein of unknown function (transcription factor) –ROGDI. Patients with an autosomal recessive mutation in this gene exhibit Kohlschütter-Tönz Syndrome, displaying epilepsy, severe psychomotor regression, and amelogenesis imperfecta symptoms. Using the approach of gene targeting we have created an equivalent mouse model for this disease. The phenotypic correlations between mouse and human models will help to define the etiology of the disease and to adapt its management.
The Ph.D. research project will involve analysis of this mutant, and postnatal models including both inducible brain and epithelial-specific deletions of ROGDI. To understand neurodegenerative and enamel deficits, the candidate will conduct comparative genomic studies. Whole genome RNA-sequencing, ChiP-Seq, combined with bioinformatic approaches should uncover a ROGDI transcriptional network. The physiological relevance of the genes found by transcriptome analysis will be validated by in situ hybridization, immunohistochemistry and functional genetics. Selecting key targets, the candidate will attempt functional rescue using in utero electroporation and pharmacological treatment of epilepsy to develop translational approaches.
Thesis supervisor : Agnès Bloch-Zupan
Date limite de candidature : 1 novembre 2018