Pavel Krejčí Group: Cell Signaling
DEPARTMENT OF BIOLOGY RESEARCH GROUP
Our research on FGFR3-related skeletal dysplasia
The major focus of our research for over 15 years has been to dissect the mechanisms of fibroblast growth factor (FGF) signaling. We are interested in pathological FGF-receptor (FGFR) signaling in disease, namely the skeletal disorders caused by activating mutations in FGFR3 (hypochondroplasia, achondroplasia, thanatophoric dysplasia, SADDAN). Our studies encompass many different areas of the FGF field including expression of FGF ligands in vivo, mechanisms of FGF/FGFR-mediated regulation of cell function, molecular mechanisms of FGFR signal transduction, biochemistry of FGFR kinase activation, development of FGFR inhibitors, and others. In our research, we actively collaborate with other scientists worldwide, including those from Norway (Dr. A. Wiedlocha, Oslo University), USA (Dr. D. Krakow, University of California Los Angeles; Dr. K. Hristova, John Hopkins University, Baltimore) and the Czech Republic (Dr. L. Trantirek, Masaryk University CEITEC, Brno; Dr. P. Konik, University of South Bohemia, Ceske Budejovice; Dr. M. Buchtova, Masaryk University).
The current lab projects related to achondroplasia address three important and poorly understood areas of FGFR3 function in chondrocytes: (1) the composition of signaling complexes proximal to activated FGFR3 at the cell membrane, (2) the nature of molecular effectors utilized by FGFR3 signaling to mediate specific cell functions, and (3) the mechanisms by which FGFR3 regulates chondrocyte differentiation. In addition to understanding the basic mechanics of FGFR3 signal transduction, we also focus on development of novel ways to target FGFR3 therapeutically. In the past, we characterized one novel small chemical inhibitor of FGFR3, as well as the mechanism of inhibition of FGFR3 signaling by a biological pathway, i.e. the C-natriuretic peptide (CNP) signaling. The latter work provided the basis for our collaboration with Biomarin Pharmaceuticals (Novato, CA) on development of a CNP analogue as a treatment for achondroplasia. The work on therapeutic targeting of FGFR3 never ceases, and we currently have several projects addressing novel avenues of FGFR3 inhibition.