Full-Time Faculty

 

Professor Shu-Wha Lin

Title:

Professor of Department of Clinical Laboratory Science and Medical Technology, College of Medicine, N.T.U.
Senior Scientist, Department of Internal Medicine
Supervisor, Department of Laboratory Medicine, National Taiwan University Hospital
Principal Investigator, Transgenic Mouse Models Core Facility, National Research Program for Genomic Medicine

 

Education:

B.S., School of Medical Technology, National Taiwan University
M.S., Graduate Institute of Microbiology, College of Medicine, National Taiwan University
Ph.D., Biology department, University of North Carolina at Chapel Hill, U. S. A

 

 

E-mail: mtshuwha@ntu.edu.tw

 

 

Specialty:

1. Transgenic and gene-targeted mice
2. Molecular hematology and coagulation
3. Laboratory diagnosis of hemostasis and thrombosis

 

Prof. Lin was trained as a hematologist specialized in Thrombosis and Hemostasis. In 1994 she visited Pasteur Institute in France as Visiting Scholar at the Department of Visiting Scientist, where she began her carrier in Transgenic Technology. In 2003, she received a national grant and set up the Transgenic Mouse Model Core facility. The facility has served more than 180 researchers and generated more than 300 knockout and knockin mouse lines since then.
In the past five years, in addition to operating the Transgenic Mouse Core Facility, Prof. Lin has studied the function and underlying molecular mechanisms of genes using various transgenic mouse models, including models of the central nervous system, blood coagulation, and cancer.
A. Nervous system:
The principal investigator’s team has initiated neuroscience research. In collaboration with President Yang of National Taiwan University, we found impaired spatial learning in mice that were deficient in CRMP-1 (Collapse Response Mediator Protein 1) and discovered the underlying mechanism (Su et al., 2007, J Neurosci 27, 2513-2524). In addition, we generated Cul4b knockout mice that mimic the symptoms of a human X-linked intellectual disorder (XLID). The mouse model also exhibited spatial and learning impairment and can serve as a useful tool to investigate intellectual deficit. We are continuing our neuroscience research by studying the SCN1A gene in a disease mouse model of Dravet syndrome. Dravet syndrome is an autosomal dominant disease that is caused by de novo mutations in the SCN1A gene. We have generated a Dravet syndrome mouse model in collaboration with OPKO Inc. and several researchers. The heterozygous mice display high mortality, spontaneous seizures and hyperthermia-induced seizures that mimic the main symptoms of Dravet patients. We have used this disease mouse model as an in vivo drug-screening and validation platform. We have also set up two in-vitro cell culture systems to screening for new compounds that can either overcome the premature stop codons occurred in more than 70% Dravet syndrome patients or those that can up-regulate the wild-type (WT) SCN1A allele to increase the SCN1A mRNA expression. Using these two different cell-based screening platforms, and with the help of the core facility of the Ultra-High Throughput Screening service in the Genomics Research Center (GRC), Academia Sinica (AS), we have identified potential hit compounds.
B. Blood Coagulation
Study of Factor IX in a disease mouse model of Hemophilia
Improving the treatment of hemophilia faces challenges including the need to fulfill the demand for viral-free recombinant protein products worldwide, creating efficient and safe DNA delivery vehicles for use in gene therapy, and preventing the development of inhibitors to protein products and delivery vehicles. In an attempt to reach these goals, we focused on reducing the amount of protein and delivery vector needed for effective hemophilia treatment. We created a novel human IX variant with higher clotting activities than the WT and that exhibits therapeutic efficacy at much lower levels (Recombinant human factor IX and use thereof, US Patent No. 7888067 and International Appl. No.: PCT/ US2008/050331 International Pub. No.: WO 2008/118507). The concentration of delivery vehicles carrying factor IX codons specifying the higher factor IX clotting activity can thus also be reduced. The factor IX molecule was named Factor IX (FIX)-Triple. FIX-Triple (V86A/E277A/R338A) exhibited 13-fold and 7- to 9-fold higher specific clotting activity than WT factor IX (FIX-WT) in in vitro studies and in in vivo protein infusion and gene delivery in hemophilia B mice, respectively. These studies suggest that FIX-Triple is a potential therapeutic substitute for FIX-WT.
Study of Hespin
Hepsin is type-II serine protease that is expressed at high levels in liver. Hepsin has been suggested to be involved in prostate cancer metastasis. We have successfully generated hepsin knockout mice (Yu et al., 2000, Thromb Haemost 84, 865-70). We found that hepsin is associated with HGF/c-Met signaling during the regulation of connexin expression that affects liver sinusoidal width.

Publication (2010~)

1. Lin CN, Kao CY, Miao CH, Hamaguchi N, Wu HL, Shi GY, High KA, and Lin SW. (2010). Generation of a novel factor IX with augmented clotting activities in vitro and in vivo. J Thromb Haemost 8, 1773-1778.
2. Kao CY, Lin CN, Yu IS, Tao MH, Wu HL, Shi GY, Yang YL, and Lin SW. (2010). FIX-Triple, a factor IX variant with augmented clotting activity, does not increase the risk of thrombosis in mouse models. Thromb Haemost 104, 355-365.
3. Wu YM, Kao CY, Huang YJ, Yu IS, Lee HS, Lai HS, Lee PH, Lin CN, and Lin SW. (2010). Genetic Modification of Donor hepatocyte Improves therapeutic Efficacy for hemophilia B in mice. Cell Transplant. 19, 1169-80.
4. Yang S-S, Lo Y-F, Wu C-C, Lin SW, Yeh C-J, Chu P, Sytwu H-K, Uchida S, Sasaki S, Lin S-H Lin. (2010) SPAK knockout mice manifest Gitelman’s syndrome and impaired vasoconstriction. J Am Society of Nephrology 21, 1868-1877.
5. Yang S-S, Lo YF, Yu I-S, Lin SW, Chang T-H, Hsu YJ, Chao T-K, Sytwu H-K, Uchida S, Sasaki S, and Lin S-H (2010). Generation and analysis of thiazide-sensitive Na+-Cl- cotransporter (NCC) S707X knockin mouse as a model of Gitelman syndrome. Human Mutation 31, 1304-1315.
6. Yang YL, Lin SR, Chen JS, Hsiao CC, Lin KH, Sheen JM, Cheng CN, Wu KH, Lin SW, Yu SL, Chen HY, Lu MY, Chang HH, Yen CT, Lin JF, Su YH, Li YP, Lin CY, Jou ST, Lin DT. (2011) Multiplex reverse transcription-polymerase chain reaction as diagnostic molecular screening of 4 common fusion chimeric genes in Taiwanese children with acute lymphoblastic leukemia. J Pediatr Hematol Oncol. 32, e323-330.
7. Lin YH, Chou CK, Hung YC, Yu IS, Pan HA, Lin SW, Kuo PL. (2011) SEPT12 deficiency causes sperm nucleus damage and developmental arrest of preimplantation embryos. Fertil Steril. 95, 363-365.
8. Lo Y-F, Yang S-S, Seki G, Yamada H, Horita S, Yamazaki O, Fujita T, Usui T, Tsai J-D, Yu I-S, Lin SW, Lin S-H. (2011) Severe Metabolic Acidosis Causes Early Lethality in kNBC1 W516X Knock-in Mice as a Model of Human Isolated Proximal Renal Tubular Acidosis. Kidney Int. 79, 730-741.
9. Kao CY, Lin CN, Yang YL, Hamaguchi N, Yang SJ, Shen MC, Kao JT, Lin SW. (2011) Characterization of factor IX with a glycine-to-valine missense mutation at residue 190 in a patient with severe hemophilia B. Thromb Haemost 105, 616-626.
10. Huang HP, Hong CL, Kao CY, Lin SW, Lin SR, Wu HL, Shi GY, You LR, Wu CL, Yu IS. (2011) Gene targeting and expression analysis of mouse Tem1/endosialin using a lacZ reporter. Gene Expr Patterns. 11, 316-326.
11. Lin S-H, Yu I-S, Jiang S-T, Lin SW, Chu P, Chen A, Sytwu HK, Soharaf E, Uchidaf S, Sasakif S, Yang S-S. (2011) Impaired phosphorylation of Na+-K+-2Cl− cotransporter by oxidative stress-responsive kinase-1 deficiency manifests hypotension and Bartter-like syndrome. Proc Natl Acad Sci U.S.A. 108,17538-17543.
12. Lu YC, Wu CC, Shen WS, Yang TH, Yeh TH, Chen PJ, Yu IS, Lin SW, Wong JM, Chang Q, Lin X, Hsu CJ. (2011) Establishment of a Knock-In Mouse Model with the SLC26A4 c.919-2A>G Mutation and Characterization of Its Pathology. PLoS ONE 6, e22150.
13. Yang YL, Hung CC, Chen JS, Lin KH, Jou ST, Hsiao CC, Sheen JM, Cheng CN, Wu KH, Lin SR, Yu SL, Chen HY, Lu MY, Wang SC, Chang HH, Lin SW*, Su YN*, Lin DT*. (2011) IKZF1 deletions predict a poor prognosis in children with B-cell progenitor acute lymphoblastic leukemia: A multicenter analysis in Taiwan. Cancer Sci. 102, 1874-1881.
14. Yang YL, Hsiao CC, Chen HY, Lin KH, Jou ST, Chen JS, Chang TK, Sheen JM, Yu SL, Lu MY, Cheng CN, Wu KH, Wang SC, Wang JD, Chang HH, Lin SR, Lin SW, Lin DT. (2012) Absence of biallelic TCRγ deletion predicts induction failure and poorer outcomes in childhood T-cell acute lymphoblastic leukemia. Pediatr Blood Cancer 58, 846-851.
15. Hsu YC, Huang HP*, Yu IS, Su KY, Lin SR, Lin WC, Wu HL, Shi GY, Tao MH, Kao CH, Wu YM, Martin PE, Lin SY, Yang PC and Lin SW. (2012) Serine protease hepsin regulates hepatocyte size and hemodynamic retention of tumor cells via hepatocyte growth factor signaling. Hepatology 56, 1913-1923.
16. Ma CY, Shi GY, Shi CS, Kao YC, Lin SW, Wu HL. (2012) Monocytic thrombomodulin triggers LPS- and gram-negative bacteria-induced inflammatory response. J Immunol 188, 6328-6337.
17. Chen CY, Tsai MS, Lin CY, Yu IS, Chen YT, Lin SR, Juan LW, Chen YT, Hsu HM, Lee LJ and Lin SW. (2012) Rescue of the genetically-engineered Cul4b mutant mouse as a potential model for human X-linked mental retardation. Human Mol Genetics 21, 4270-4285.
18. Chen Y-T, Tsai M-S, Yang T-L, Ku AT, Huang K-H, Huang C-Y, Chou F-J, Fan H-H, Hong J-B, Yen S-T, Wang W-L, Lin C-C, Hsu Y-C, Su K-Y, Jang C-W, Behringer RR, Favaro R, Nicolis SK, Chien CL, Lin SW, and Yu I-S. (2012) R26R-GR: a Cre-activable Dual Fluorescent Protein Reporter Mouse. PLoS ONE 7, e46171.
19.Chou SH, Ko BS, Chiou JS, Hsu YC, Tsai MH, Chiu YC, Yu IS, Lin SW, Hou HA, Kuo YY, Lin HM, Wu MF, Chou WC, Tien HF. A knock-in Npm1 mutation in mice results in myeloproliferation and implies a perturbation in hematopoietic microenvironment. PLoS One. 2012, 7, e49769.
20. Kao CY, Yang SJ, Tao MH, Jeng YM, Yu IS, Lin SW. (2013) Incorporation of the factor IX Padua mutation into FIX-Triple improves clotting activity in vitro and in vivo. Thromb Haemost, 110, 244-256.
21. Yang S-S, Fang Y-W, Tseng M-H, Chu P-Y, Yu I-S, Wu H-C, Lin SW, Chau T, Uchida S, Sasaki S, Liu Y-F, Sytwu H-K, Lin S-H. (2013) Defective NCC phosphorylation impairs its stability and prevents pseudohypoaldosteronism type II. J Am Soc Nephrology 24, 1587-1597.
22. Kuo P-L , Chiang HS , Wang YY , Kuo YC , Chen MF , Yu IS, Teng YN, Lin SW and Lin YH. (2013) SEPT12-Microtubule Complexes Are Required for Sperm Head and Tail Formation. Int. J. Mol. Sci. 14, 22102-22116
23. Ho BC, Yu IS, Lu LF, Rudensky A, Chen HY, Tsai CW, Chang YL, Wu CT, Chang LY, Shih SR, Lin SW, Lee CN, Yang PC, Yu SL. (2014) Inhibition of miR-146a prevents enterovirus-induced death by restoring the production of type I interferon. Nature Commun. 5, 3344.
24.Hong JB, Chou FJ, Ku AT, Fan HH, Lee TL, Huang YH, Yang TL, Su IC, Yu IS, Lin SW, Chien CL, Ho HN, Chen YT. (2014). A nucleolus-predominant piggyBac transposase, NP-mPB, mediates elevated transposition efficiency in mammalian cells. PLoS One. 9, e89396.
25. Hung MH, Jian YR, Tsao CC, Lin SW, Chuang YH. (2014). Enhanced LPS Induced Peritonitis in Mice Deficiency of Cullin 4B in Macrophages. Genes and Immunity 15, 404-12.
26.Tseng WL, Chen TH, Huang CC, Huang YH, Yeh CF, Tsai HJ, Lee HY, Kao CY, Lin SW, Liao HR, Cheng JC, Tseng CP. (2014). Impaired thrombin generation in Reelin-deficient mice: a potential role of plasma Reelin in hemostasis. J Thromb Haemost. Sep 26. doi: 10.1111/jth.12736. [Epub ahead of print]

27. Tsai MS, Lee ML, Fan HH, Yu IS, Chen YT, You JY, Chang FC, Hsiao JH, Khorkova O, Liou HH, Yanagawa Y, Lee LJ, Lin SW. (2015) Functional and structural deficits of the dentate gyrus network coincide with emerging spontaneous seizures in an Scn1a mutant Dravet Syndrome model during development. Neurobiology of Disease (Accepted)