Function of the transcription factors Olig3 and Lbx1 in brainstem respiratory nuclei

Project Reference: 302477
Activity Code: FP7-PEOPLE-2011-IEF
Coordinator:Max-Delbrück-Centrum für Molekulare Medizin (MDC) Berlin-Buch

Abstract

Congenital Central Hypoventilation Syndrome (CCHS also known as Ondines curse) is a lethal condition in newborn children characterized by respiratory arrest during sleep. The understanding of breathing disorders is currently limited due to our scarce knowledge of the developmental program that controls the establishment of respiratory centres in the brainstem. The solitary tract (NTS) and retro-trapezoid (RTN) nuclei are essential for the relay and sensing of O2 and CO2 levels, respectively. NTS also participates in the initiation of inspiration, whereas RTN acts as an oscillator for the generation of respiratory rhythm activity. In the present proposal, I suggest to investigate the function of Olig3 and Lbx1 in development and physiology of the NTS and RTN, respectively.

Olig3 is proposed to generate NTS neurons. My preliminary observations reveal that Olig3 (Olig3-/-) mutant mice die within few hours after birth from an apparent failure to maintain respiration. Anatomical examinations showed absence of NTS in Olig3-/- mice, suggesting that they die from a failure of the central relay neurons that transmit O2 information and control inspiration. Lbx1 is of relevance for the development of the respiratory rhythm oscillator and CO2 sensor. In a genetic screen of patients with CCHS, I identified a frame-shift mutation in exon 2 of their LBX1 gene. To re-create this condition in mice and study its consequences further, I have generated a targeting vector to introduce this mutation into the mouse genome. Given the relevance of this presumptive pathological mutation for humans, it is necessary to understand its implications in development of respiratory centres such as the RTN. In envisage that the knowledge gained will contribute to defining strategies for future pharmacological treatment of breathing disorders.
This project will represent an excellent opportunity to establish myself as a leading scientist in the field of mouse genetics and developmental neurobiology.

Project Details: 

Start Date: 2012-07-01
End Date: 2014-06-30
EU Contribution: EUR 167 390
Total Costs: EUR 167 390
Programme Acronym: FP7-People
Subprogramme Area: FP7-PEOPLE-2011-IEF
Funding Scheme: Intra-European Fellowships (IEF)
Administrative Contact Person: Sabine BAARS (Dr)
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