Here we report our study on one of the skeletal diseases, the Apert syndrome, which occurs at one in 65,000 live births in human. We first introduced a Ser252Trp mutation that is found in human Apert patients, to mouse FGFR2 gene. The FGFR2-Ser252Trp mutant mice displayed phenotypes mimicking the human Apert disease. We then use this mouse model to test preventivetherapeutic approaches to see if the disease can be prevented or cured. We show that a small hairpin RNA (shRNA), targeting the FGFR2-S252W mutant form mRNA in this mouse model, completely inhibits Apert-like craniosynostosis and the related defects. We further show that restoration of normal FGFR2 signaling is manifested by an alteration of ERK12 activity, implicating ERK and its downstream genes in disease expressivity. Furthermore, treatment of mutant mice with an ERK inhibitor results in a complete cure of mutant phenotypes. These results illustrate an unknown pathogenic role of ERK activation in the FGFR2-S252W-associated craniosynostosis and represent a new concept of shRNA-mediated therapy for diseases caused by gain of functions associated with activating point mutations in human genome.

Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2011
Total Cost
$465,825
Indirect Cost
City
State
Country
Zip Code
Lee, M-H; Lahusen, T; Wang, R-H et al. (2012) Yin Yang 1 positively regulates BRCA1 and inhibits mammary cancer formation. Oncogene 31:116-27
Zhu, Min; Yi, Ming; Kim, Chang Hee et al. (2011) Integrated miRNA and mRNA expression profiling of mouse mammary tumor models identifies miRNA signatures associated with mammary tumor lineage. Genome Biol 12:R77
Sato, Yukiyasu; Heimeier, Rachel A; Li, Cuiling et al. (2011) Extracellular domain of CD98hc is required for early murine development. Cell Biosci 1:7
Choksi, Swati; Lin, Yong; Pobezinskaya, Yelena et al. (2011) A HIF-1 target, ATIA, protects cells from apoptosis by modulating the mitochondrial thioredoxin, TRX2. Mol Cell 42:597-609
Hsiao, Yi-Hsuan; Deng, Chuxia; Mason, Jeffrey T et al. (2011) Hidden malignant cells within leukocyte aggregates: seeds for invasive and metastatic cancer? Cancer Epidemiol 35:475-9
Deng, Chuxia; Liu, Hanqin (2010) An unknown piece of early work of nuclear reprogramming in fish eggs. Int J Biol Sci 6:190-1
Liu, Wenli; Yan, Ming; Liu, Yueqin et al. (2010) Olfactomedin 4 down-regulates innate immunity against Helicobacter pylori infection. Proc Natl Acad Sci U S A 107:11056-61
Huang, Xiao R; Chung, Arthur C K; Yang, Fuye et al. (2010) Smad3 mediates cardiac inflammation and fibrosis in angiotensin II-induced hypertensive cardiac remodeling. Hypertension 55:1165-71
Baur, Joseph A; Chen, Danica; Chini, Eduardo N et al. (2010) Dietary restriction: standing up for sirtuins. Science 329:1012-3; author reply 1013-4
Azhar, Mohamad; Wang, Pei-Yu; Frugier, Tony et al. (2010) Myocardial deletion of Smad4 using a novel ? skeletal muscle actin Cre recombinase transgenic mouse causes misalignment of the cardiac outflow tract. Int J Biol Sci 6:546-55

Showing the most recent 10 out of 20 publications