研究成果
1. 世界第一例脊髓肌肉萎縮症小鼠模式
脊髓肌肉萎縮症乃嬰兒致死率第二高的隱性遺傳疾病,本研究室所建立的這項動物模式不僅是世界首例,而且是目前已經建立之相關動物模式中和人類發病模式相似性最高者。利用此疾病小鼠模式,我們也已篩選出數種深具潛力的藥物,其中我們測試出有治療潛力的HDAC(histone deactylation)抑制劑,最近更被歐美臨床初步試驗對病人症狀有舒緩之效果。目前,我們也已與美國「脊髓肌肉萎縮症基金會」簽訂合作協議,將此小鼠模式提供給歐美研究學者作藥物篩選的研究,相信將更有利於日後對治療藥物的研發或臨床病人的照顧。另外,透過研究HDAC 抑制劑作用的分子機制,我們篩選
到一STAT5 蛋白質,在藥物的處理下可增加其表現量, STAT5 可促進SMA 致病蛋白質SMN 的表現,增加運動神經軸突的延展,而對SMA 運動神經細胞的缺陷加以治療。在以VPA 藥物治療罹患第三型SMA 小鼠的研究中,我們發現此藥物不但提升了脊髓中SMN 蛋白質的表現量,還具有抗細胞凋亡能力以及保護神經之效果,可以減緩運動神經元的退化,使SMA 小鼠具有較好的活動能力及減少肌肉萎縮的情形發生。
2. 自體顯性多囊性腎臟病的小鼠模式
根據統計,台灣每3 萬5 千個洗腎病患中,至少有1 千人罹患自體顯性多囊性腎臟病,在歐美國家,這種病人甚至佔慢性腎功能衰竭的十分之一。我們之研究室已利用降低主要致病基因Pkd1 在小鼠體內的表現量而成功的建立了此動物模式,而且此動物模式優於目前世界上已經建立之各相關模式。我們目前正在進行以rapamycin 治療病鼠,發現治療後的病鼠其多囊腎的囊腫症狀改善約24% ,腎臟功能也獲改善,原本只能存活約23 天的老鼠經治療後也可一直持續存活下來。這些研究結果已著手整理,將投稿進行發表。最重要的是我們也和成大醫學院腎臟科主治醫生密切合作,希望結合臨
床病人之樣本與動物模式之研究,期盼能儘快為此類病患找到治療之道。
3. 中風病人之幹細胞治療模式
我們早期將幹細胞打入老鼠體內,再以核磁共振攝影追蹤,結果發現幹細胞可以讓老鼠的腦神經細胞進行修復與再生,因此我們聯想到,或許可藉
由誘發生長激素分泌,促使自體的幹細胞動員而進行細胞的修復。其後我們採用已經使用二十多年的老藥-顆粒球促進生長激素G-CSF 進行動物試驗,
發現這個藥物的確可以激發體內的幹細胞,對受損的腦細胞進行修補,並促使腦神經與血管再生。接下來與慈濟醫院合作進行的人體試驗中,十名中風
7天內的患者在治療之後,我們也觀察到有高於60% 的恢復情形。
另外,我們也發現一個廣泛存在於各個組織表現的分子-secretoneurin (SN),於缺血性中風患者腦部的陰暗區域(penumbra area)表現量有顯著提升
之情形,進一步之研究更發現SN 不僅對受傷神經細胞具有保護的作用,也會誘引幹細胞往受損腦部區域 ,並分化形成新的神經與血管細胞抑制腦部梗塞區域的擴張,增進神經細胞的可塑性。
研究著作
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- Tsao, P. N., Li, H., Wei, S. C., Ko, M. L., Chou. H. C., Hsieh, W. S. and Hsieh, F. J. (2004) Expression of angiogenic factors and their receptors in postnatal mouse developing lung. J. Formos Med. Assoc. 103, 137-143.
- 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.
- 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.
- Chiu, S. T., Hsieh, F. J., Chen, S. W., Chen, C. L., Shu, H. F. and Li, H. (2005) Clinicopathologic 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.
- 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.
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- Hsu, S. H., Hsieh-Li, H. M., Huang, H. Y., Huang, P. H. and Li, H. (2005) bHLH-zip transcription factor Spz1 mediates MAPK cell proliferation, transformation and tumorigenesis. Cancer Res. 65, 4041-4050.
- 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.
- Grondard, C., Biondi, O., Armand, A. S., Lecolle, S., Della Gaspera, B., Pariset, C., Li, H., Gallien, C. L., Vidal, P. P., Chanoine, C. and Charbonnier, F. (2005) Regular exercise prolongs survival in a type 2 spinal muscular atrophy model mouse. J. Neurosci. 25, 7615-7622.
- 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 reduces ischemic injury in a stroke rat model. J. Neurosci. 25, 8967-8977.
- Tsai, L. K., Tsai, M. S., Shyue, S. K., Hwu, W. L. and Li, H. (2005) Adenoviral interneuronal transportation after retrograde gene transfer in mice. Brain Res. Mol. Brain Res. 142, 151-155.
- 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 (invited review).
- Jiang, S. T., Chiou, Y. Y., Wang, E., Lin, H. K., Lin, Y. T., Chi, Y. C., 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.
- 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.
- 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. Can. Med. Assoc. J. 174, 927-933.
- 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.
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- Lo, R. Y., Shyu, W. C. and Li, H. (2006) Long-duration sCJD with PRNP codon 129 methionine homozygosity and cerebral cortical plaques. Neurology 66, 1944-1945.
- 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. 21, 1209-1216 (invited review).
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- Ding D. C., Shyu, W. C., Lin, S. Z., and Li, H. (2006) Current concepts in adult stem cell therapy for stroke. Curr. Med. Chem. 13, 3565-3574 (invited review).
- Liew, C. L., Shyu, W. C., Tsao, W. L., and Li, H. (2006) Intravascular lymphomatosis mimicks a cerebral demyelinating disorder. Acta Neurol. Taiwan. 15, 264-8.
- Shyu, W. C., Chen, C. P., Lin, S. Z., Lee, Y. J. and Li, H. (2007) Efficient tracking of non-iron-labeled mesenchymal stem cells with serial MRI in chronic stroke rats. Stroke 38, 367-374.
- Ting, C. H., Lin, C. W., Wen, S. L., Hsieh-Li, H. M. and Li, H. (2007) Stat5 constitutive activation rescues defects in spinal muscular atrophy. Hum. Mol. Genet. 16, 499-514.
- Chang, Y. C., Shyu, W. C., Lin, S. Z. and Li, H. (2007) Regenerative therapy for stroke. Cell Transplantation 16, 171-181 (invited review).
- Ding, D. C., Shyu, W. C., Lin, S. Z., and Li, H. (2007) The role of endothelial progenitor cells in ischemic cerebral and heart diseases. Cell Transplantation 16, 273-284 (invited review).
- Cheng, W. C., Hsieh-Li, H. M., Yeh, Y. J. and Li, H. (2007) Mice lacking the Obox6 homeobox gene undergo normal early embryonic development and are fertile. Dev. Dyn. 236, 2636-2642. ?
- Lai, D. M., ?Tu, Y. K., Hsieh, Y. H., Hsu, W. M. Lee, C. C., Cheng, W. C., Hsieh, F. J. and Li, H. (2007) Angiopoietin-like protein 1 expression is related to intermuscular connective tissue and cartilage development. Dev. Dyn. 236, 2643-2652.
- Ding, D. C., Shyu, W. C., Chiang, M. F., Lin, S. Z., Chang, Y. C., Wang, H. J., Su, C. Y. and Li, H. (2007) Enhancement of neuroplasticity through upregulation of β1-integrin in human umbilical cord-derived stromal cell implanted stroke model. Neurobiol. Dis. 27, 339-353.
- Lo, R. Y., Shyu, W. C., Lin, S. Z., Wang, H. J., Chen, S. S. and Li, H. (2007) New molecular insights into cellular survival and stress responses: neuroprotective role of cellular prion protein (PrPC). Mol. Neurobiol. 35, 236-244 (invited review).
- Hsiao, J. K., Tai, M. F., Chu, H. H., Chen, S. T., Li, H., Lai, D. M., Hsieh, S. T., Wang, J. L. and Liu, H. M. (2007) Magnetic nanoparticle labeling of mesenchymal stem cells without transfection agent: cellular behavior and capability of detection with clinical 1.5 T magnetic resonance at the single cell level. Magn. Reson. Med. 58, 717-24.
- Tsai, L. K., Yang, C. C., Hwu, W. L. and Li, H. (2007) Valproic acid treatment in six patients with spinal muscular atrophy. Eur. J. Neurol. 14, e8-9.
- Shyu, W. C., Lin, S. Z., Chiang, M. F., Chen, D. C., Su, C. Y., Wang, H. J., Liu, R. S., Tsai, C. H. and Li, H. (2008) Secretoneurin promotes neuroprotection and neuronal plasticity via the Jak2-Stat3 pathway in murine models of stroke. J. Clin. Invest. 118, 133-148.
- Lai, D. M., Li, H., Lee, C. C., Tzeng, Y. S., Hsieh, Y. H., Hsu, W. M., Hsieh, F. J., Cheng, J. T. and Tu, Y. K. (2008) Angiopoietin-like protein 1 decreases blood brain barrier damage and edema following focal cerebral ischemia in mice. Neurochem. Int. 52, 470-477.
- Biondi, O., Grondard, C., Lecolle, S., Deforges, S., Pariset, C., Lopes, P., Cifuentes-Diaz, C., Li, H., della Gaspera, B., Chanoine, C. and Charbonnier, F. (2008) Exercise-induced activation of NMDA receptor promotes motor unit development and survival in a type 2 spinal muscular atrophy model mouse. J. Neurosci. 28, 953-62.
- Shyu, W. C., Lin, S. Z., Yen, P. S., Su, C. Y., Chen, D. C., Wang, H. J. and Li, H. (2008) Stromal cell-derived factor 1α (SDF-1α) promotes neuroprotection, angiogenesis and mobilization/homing of bone marrow-derived cells in stroke rats. J. Pharmacol. Exp. Ther.324, 834-49.
- Chen, C. P., Lee, M. Y., Huang, J. P., Aplin, J. D., Wu, Y. H., Hu, C. S., Chen, P. C., Li, H., Hwang, S. M., Liu, S. H. And Yang, Y. C. (2008) Trafficking of multipotent mesenchymal stromal cells from maternal circulation through the placenta involves VEGFR-1 and integrins. Stem Cells 26, 550-561.
- Shyu, W. C., Liu, D. D., Lin, S. Z., Li, W. W., Su, C. Y., Chang, Y. C., Wang, H. J., Wang, H. W., Tsai, C. H. and Li, H. (2008) Implantation of olfactory ensheathing cells promotes neuroplasticity in murine models of stroke. J. Clin. Invest. 118, 2482-2495.
- Han, C. L., Chien, C. W., Chen, W. C., Chen, Y. R., Wu, C. P., Li, H. and Chen, Y. J. (2008) A multiplexed quantitative strategy for membrane proteomics: Opportunities for mining therapeutic targets for autosomal-dominant polycystic kidney disease. Mol. Cell. Proteomics. Oct;7(10):1983-97.
- Tsai, L. K., Tsai, M. S., Ting, C. H., Wang, S. H. and Li, H. (2008) Restoring Bcl-xL levels benefits a mouse model of spinal muscular atrophy. Neurobiol. Dis. 2008 Sep;31(3):361-7.
- Tsai, L. K., Tsai, M. S., Ting, C. H. and Li, H. (2008) Multiple therapeutic effects of valproic acid in spinal muscular atrophy model mice. J. Mol. Med. Nov;86(11):1243-54.
- Jiang ST, Chiou YY, Wang E, Lin HK, Lee SP, Lu HY, Wang CK, Tang MJ, Li H. (2008) Targeted disruption of Nphp1 causes male infertility due to defects in the later steps of sperm morphogenesis in mice. Hum Mol Genet. Nov 1;17(21):3368-79.
- Bose JK, Wang IF, Li H, Tarn WY, Shen CK. (2008) TDP-43 overexpression enhances exon 7 inclusion during the survival of motor neuron pre-mRNA splicing. J Biol Chem. Oct 24;283(43):28852-9.
- Chen WC, Tzeng YS, Li H. (2008) Gene expression in early and progression phases of Autosomal Dominant Polycystic Kidney Disease. BMC Res Notes. 2008 Dec 21;1(1):131.
- Tsai LK, Yang CC, Ting CH, Su YN, Hwu WL, Li H. Correlation of survival motor neuron expression in leukocytes and spinal cord in spinal muscular atrophy. J Pediatr. Feb;154(2):303-5.
- Jiang ST, Chiou YY, Wang E, Chien YL, He HH, Tsai FJ, Lin CY, Tsai SP, Li H. (2009) Essential Role of Nephrocystin in Photoreceptor Intraflagellar Transport in Mouse. Hum Mol Genet. Feb 9. [Epub ahead of print]
- Shyu WC, Li KW, Peng HF, Lin SZ, Liu RS, Wang HJ, Su CY, Lee YJ, Li H. (2009) Induction of GAP-43 modulates neuroplasticity in PBSC (CD34(+)) implanted-Parkinson's model. J Neurosci Res. Feb 23. [Epub ahead of print]