Fibroblast growth factor receptors (FGFRs) have crucial functions in differentiation, angiogenesis, cell migration and development. Mutations in FGFRs have been shown to cause dominantly inherited human skeletal abnormalities and other disorders. In particular, the achondroplasia class of chondrodysplasias is comprised of the most common genetic forms of dwarfism in humans. Its members, achondroplasia (ACH), hypochondroplasia (HCH) and thanatoporic dysplasia types I and II (TDI and TDII), are caused by distinct mutations of fibroblast growth factor receptor 3 (FGFR3) which retard skeletal growth and development. The molecular mechanism and mediators of these FGFR3-related growth abnormalities are unclear. We have shown that the mutant TDII FGFR3 has a constitutive tyrosine kinase activity that could specifically activate STAT1 both in vitro and in vivo. Furthermore, TDII FGFR3-induced STAT1 activation was correlated with translocation of STAT1 to the nucleus, expression of cell cycle inhibitor p21WAF1/CIP1 and cell growth arrest in tissue culture cells and in the cartilage cells from the TDII fetus. These results have shown, for the first time, that abnormal STAT activation and p21WAF1/CIP1 expression may be responsible for the TDIIFGFR3-caused bone disease. Based on these discoveries, it is necessary to expand our research work on the detailed molecular mechanisms of FGFR signal transduction, and to further reveal the complicated molecular basis of mutant FGFR- associated abnormalities. In this application, I propose the following specific aims: 1) To investigate the possible programmed cell death (apoptosis) induced by the expression of mutant FGFR3. To determine whether STAT1 activation and p21 expression are involved in the induction of apoptosis. 2) To reveal molecular mechanisms of STAT1 activation by the TDII receptor and search for other possible signaling molecules that may also play a role in the mutant FGFR3 function. 3) To study molecular mechanisms of developmental disorders caused by mutant ACH, HCH, and TDI receptors of FGFR3. We will determine whether the abnormal STAT activation is also involved in these disorders. We will also test whether STAT1 activation is one of the outcomes of constitutive activation of other tyrosine kinases. 4) To generate mouse models using TDII and ACH knock-in technique. These mice will be used for in vivo test for our hypothesis and for potential therapeutic studies. I believe that the experiments proposed in this application represent a novel and important dimension of research that will reveal a molecular basis for FGFR-related genetic disorders. The results from these studies will also contribute to the development of the molecular therapies for these disorders in the future.
| Moh, Akira; Zhang, Wenjun; Yu, Sidney et al. (2008) STAT3 sensitizes insulin signaling by negatively regulating glycogen synthase kinase-3 beta. Diabetes 57:1227-35 |
| Moh, Akira; Iwamoto, Yoshiki; Chai, Gui-Xuan et al. (2007) Role of STAT3 in liver regeneration: survival, DNA synthesis, inflammatory reaction and liver mass recovery. Lab Invest 87:1018-28 |
| Jacoby, Jorg J; Kalinowski, April; Liu, Mu-Gen et al. (2003) Cardiomyocyte-restricted knockout of STAT3 results in higher sensitivity to inflammation, cardiac fibrosis, and heart failure with advanced age. Proc Natl Acad Sci U S A 100:12929-34 |
| Welte, Thomas; Zhang, Samuel S M; Wang, Tian et al. (2003) STAT3 deletion during hematopoiesis causes Crohn's disease-like pathogenesis and lethality: a critical role of STAT3 in innate immunity. Proc Natl Acad Sci U S A 100:1879-84 |
| Zhang, S S; Welte, T; Fu, X Y (2001) Dysfunction of Stat4 leads to accelerated incidence of chemical-induced thymic lymphomas in mice. Exp Mol Pathol 70:231-8 |
