Ph.D. Department of Developmental Biology, University of Cincinnati, USAResearch
Human disease models
1. The first mouse model in the world for spinal muscular atrophy
We have established the first mouse model for spinal muscular atrophy (SMA). SMA is the second most common fetal autosomal recessive genetic disease. These SMA mice should be useful in elucidating the pathogenic mechanisms of SMA and in designing therapeutic protocols for SMA patients. We have distributed these SMA mice to other research groups through the SMA foundation to speed up therapeutic strategy screening through this disease model. In my own laboratory, we have identified some potential drugs that can alleviate SMA symptoms in these mice. Our studies pave the way for future clinical trials with SMA patients
2. The cancer mouse model for a novel proto-oncogene
We have demonstrated that Spz1, a bHLH-zip transcription factor, acts downstream of MAPK (ERK1/2) to up-regulate cell proliferation and tumorigenesis. High levels of Spz1 expression were detected in several murine tumor cell lines and tumor samples from both human and Spz1 transgenic mice. Thus, Spz1 may act as a proto-oncogene, participating in the MAPK signal pathway, and be a potential therapeutic target in the treatment of Ras-induced tumors.
3. The mouse model for autosomal dominant polycystic kidney disease
Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common inherited life-threatening diseases characterized by the development of gradually enlarging renal cysts and a progressive loss of normal kidney tissue that can lead to chronic renal failure. We introduced a Neo cassette into intron 34 of mouse Pkd1 by homologous recombination to allow partially down-regulation pf Pkd1. The homozygous mice appear normal at birth but have small renal cysts. Cyst enlargement and interstitial fibrosis develop, recapitulating the phenomena seen in human ADPKD. The mouse models we generated for ADPKD are viable and suitable for advanced studies in the future.
Stem cell therapy for stroke
Stroke is a leading cause of death and disability worldwide; with no effective therapy currently available. We investigated whether granulocyte colony-stimulating factor (G-CSF) could promote vascular and neuronal repair in a rat model of cerebral ischemia. Rats with right middle cerebral artery (MCA) ligation receiving subcutaneous G-CSF showed less cerebral infarction and greater improvement in motor and sensory performance than vehicle-treated controls. Subcutaneous administration of G-CSF enhanced the availability of circulating hematopoietic stem cells (HSCs) to the brain and modulated their capacity for neurogenesis and angiogenesis in cerebral ischemic rats. Our study indicates that increases in bone marrow cell mobilization and targeting to the brain can reduce the volume of cerebral infarction and improve neural plasticity and vascularization. G-CSF aided stimulation of autologous stem cell engraftment might offer clinicians a novel strategy for neuronal repair in stroke and other neurodegenerative diseases.Publications
1. Hsu, S. H., Hsieh-Li, H. M. and Li, H. (2004) Dysfunctional spermatogenesis in transgenic mice over-expressing bHLH-Zip transcription
factor. Spz1. Exp. Cell Res. 294, 185-198.
2. Shyu, W. C., Lin, S. Z., Chiang, M. F., Yang, H. I. Thajeb, P. and Li, H. (2004) Neuregulin-1 reduces ischemia-induced brain damage
in rats. Neurobiol. Aging 25, 935-944.
3. Shyu, W. C., Lin, S. Z., Yang, H. I., Tzeng, Y. S., Pang, C. Y., Yen, P. S. and Li, H. (2004) Functional recovery of stroke induced
by G-CSF-stimulated stem cells. Circulation 110, 1847-1854.
4. Chiu, S. T., Hsieh, F. J., Chen, S. W., Chen, C. L., Shu, H. F. and Li, H. (2005) Clinicopathological correlation of up-regulated genes
identified using cDNA microarray and real-time RT-PCR in human colorectal cancer. Cancer Epidemiol. Biomarkers Prev. 14, 437-443.
5. Shyu, W. C., Lin, S. Z., Chiang, M. F., Pang, C. Y., Chen, S. Y., Hsin, Y. L., Thajeb, P. Lee, Y. J. and Li, H. (2005) Early-onset
Parkinson’s disease in a Chinese population 99mTc-TRODAT-1 SPECT, Parkin gene analysis and clinical study. Parkinsonism Relat.
Disord. 11, 173-180.
6. Hsu, S. H., Hsieh-Li, H. M., Huang, H. Y., Huang, P. X. and Li, H. (2005) A bHLH-zip transcription factor Spz1 mediates
MAPK cell proliferation, transformation and tumorigenesis. Cancer Res. 65, 4041-4050.
7. Shyu, W. C., Chen, C. P., Saeki, K., Kubosaki, A., Matusmoto, Y., Onodera, T., Ding, D. C., Chiang, M. F., Lee, Y. J., Lin, S. Z.
and Li, H. (2005) Hypoglycemia enhances the expression of prion protein and heat shock protein 70 in a mouse neuroblastoma cell line.
J. Neurosci. Res. 80, 887-894.
8. Shyu, W. C., Lin, S. Z., Chiang, M. F., Ding, D. C., Li, K. W., Chen, S. F., Yang, H. I. and Li, H. (2005) Over-expression of PrPC
by adenovirus-mediated gene targeting attenutes stroke injury in an ischemic rat model. J. Neurosci. 25, 8967-8977.
9. Tsai, L. K., Tsai, M. S., Shyue, S. K. Shyue, Hwu, W. L. and Li, H. (2005) Adenoviral interneuronal transportation after retrograde gene
transfer in mice. Brain Res. Mol. Brain Res. 142, 151-155.
10. Shyu, W. C., Lee, Y. J., Liu, D. D., Lin, S. Z. and Li, H. (2006) Homing genes, cell therapy and stroke. Front. Biosci. 11, 889-907
11. Jiang, S. T., Chiou, Y. Y., Wang, E., Lin, H. K., Lin, Y. T., Wang, C. K., Tang, M. J. and Li, H. (2006) Defining a link with autosomal
dominant polycystic kidney disease in mice with congenitally low expression of Pkd1. Am. J. Pathol.168, 205-220.
12. Tsai, M. S., Chiu Y. T., Wang, S. H., Hsieh-Li, H. M. and Li, H. (2006) Abolishing Trp53-dependent apoptosis does not benefit spinal
muscular atrophy model mice. Eur. J. Hum. Genet. 14, 372-375.
13. Shyu, W. C., Lin, S. Z., Lee, C. C., Liu, D. D. and Li, H. (2006) Granulocyte colony-stimulating factor for acute ischemic stroke:
a randomized controlled trial. CMAJ 174, 927-933.
14. Shyu, W. C., Lin, S. Z., Chiang, M. F., Su, C. Y. and Li, H. (2006) Intracerebral peripheral blood stem cell (CD34+) implantation
induces neuroplasticity by enhancing β1-integrin-mediated angiogenesis in chronic stroke rats. J. Neurosci. 26, 3444-3453.
15. Li, H., Tsai, M. S., Chen, C. Y., Lian, W. C., Chiu, Y. T., Chen, G. D. and Wang, S. H. (2006) A novel maternally transcribed
homeobox gene, Eso-1, is preferentially expressed in oocytes and regulated by cytoplasmic polyadenylation. Mol. Reprod. Dev. (in press).
16. Tsai, M. S., Chiu Y. T., Wang, S. H., Hsieh-Li, H. M., Lian, W. C. and Li, H. (2006) Abolishing Bax-dependent apoptosis shows beneficial
effects on spinal muscular atrophy model mice. Mol. Ther. (in press)
17. Lo, Y. Y., Shyu, W. C. and Li, H. (2006) Long-duration sCJD with PRNP codon 129 methionine homozygosity and cerebral cortical
plaques. Neurology (in press).
18. Chen, C. P., Lee, Y. J., Chiu, S. T., Shyu, W. C., Lee, M. Y., Huang, S. P. and Li, H. (2006) The application of stem cells in the
treatment of ischemic diseases. Histol Histopathol., in press (invited review).