Project ASCE

ASCE – Aberrant Splicing of CFTR Exon 9

ABSTRACT

Alternative splicing of pre-mRNAs is tightly regulated and any imbalance can change the outcome of gene expression which often leads to disease. Despite the importance of alternative splicing regulation our knowledge at the molecular level is still in its infancy hampering development of effective therapies. We plan to study the regulatory RNA-protein and protein-protein interaction networks leading to skipping of CFTR exon 9 associated with severe forms of cystic fibrosis. Structure determination of regulatory complexes by NMR spectroscopy in combination with biochemical and functional in vivo studies will be used to deepen our molecular understanding of the regulatory networks governing the proper assembly of mRNAs.  With this, we want to reveal the molecular basis of aberrant CFTR exon 9 splicing and lay a rational, structure- and function-based foundation for novel approaches to cure diseases.

Figure 1.Schematic representation of the modular RNA binding proteins known to regulate CFTR exon 9 splicing.  The name of the human proteins is shown on the left, the domain composition is shown in the middle with domain boundaries indicated and the known consensus binding sequences are shown on the right. 

PROJECT AIMS

1. Description of molecular details of RNA-protein and protein-protein interactions at the 3’ss of CFTR exon 9 determining its aberrant splicing
2. Biochemical and biophysical characterization of the interaction network at CFTR exon 9
3. Functional and structural characterization of the interaction network at CFTR exon 9
4. Screening for small molecule inhibitors which disrupt aberrant splicing of CFTR exon 9