NTUIMCB

近年研究主題

計畫性細胞死亡（Programmed Cell Death or apoptosis）、細胞遷移（cell migration）與器官發育（organogenesis）的機制

研究室簡介

本實驗室有興趣的的研究領域主要是計畫性細胞死亡(programmed cell death or apoptosis)與細胞遷移(cell migration)。（一）計畫性細胞死亡是指活體生物中的某些特定細胞在特定的時間與地點會進行細胞死亡，而這種細胞死亡的過程是由生物體內的基因來控制。調控不當的計畫性細胞死亡與神經退化症(neural degenerative disease)及細胞不當增生(cancerous growth)密切相關。但生物體如何決定那些細胞該進行計畫性細胞死亡? 如何執行計畫性細胞死亡之死刑任務? 又細胞進行計畫性細胞死亡之後，屍體如何為吞噬細胞所吞噬滅跡? (二）細胞遷移是指多細胞生物體在發育過程中，許多的細胞會離開初生地點而行走遷移到其他的特定地點，以重組生物體內細胞的位置，細胞遷移的過程是由生物體內的基因來控制：不同的遷移細胞有自己特定的遷移時間與目的地。調控不當的細胞遷移，可能影響生物體的活動或行為，嚴重的甚至會造成發育異常而致死。但進行遷移的細胞如何移動?如何穿越其他細胞的障礙？又如何知曉遷移的時間、路徑與目的地?

為探討複雜的計畫性細胞死亡與細胞遷移的機制，本實驗室採取兩種研究方式，第一是利用線蟲Caenorhabditis elegans的優勢來搜尋作用於計畫性細胞死亡與細胞遷移的新基因，第二是將線蟲的研究結果延伸到人類細胞的研究。研究的概況分述於下

一、 利用線蟲進行研究: Sydney Brenner就是因為是第一位選擇線蟲作為發育生物學模式動物，而得2002年的諾貝爾獎醫學/生理獎，顯示線蟲對發育生物學乃至醫學的研究有重大的貢獻。線蟲成虫僅有1毫米長，全身透明，且不具寄生性，在實驗室培養相當容易。線蟲具有兩大特徵，使牠在研究計畫性細胞死亡與細胞遷移的領域上具有優勢，並因此。第一是活體內(in vivo)的計畫性細胞死亡與細胞遷移研究在線蟲可達到單一細胞的解析程度。第二是線蟲固定的細胞淵源(fixed cell lineage)，使具有計畫性細胞死亡或細胞遷移變異的突變株，極易被觀察發現。本實驗室是利用線蟲的優異性，結合遺傳、分子生物與生化方法，研究計畫性細胞死亡與細胞遷移的機制。

二、 利用人類細胞培養進行研究:本實驗室更進一步將我們在線蟲所發現的實驗結果延伸到人體細胞的研究，首先我們搜尋對應於線蟲基因的人類同源基因，再利用人類細胞培養的系統，進一步探討人類同源基因的作用機制。

A. REFEREED PAPERS:

I. Cell Migration and Cell Death

1.       Wu, Y.C. and Horvitz, H.R. C. elegans phagocytosis and cell-migration protein CED-5 is similar to human DOCK180. Nature, 392, 501-504 (1998).

2.       Wu, Y.C. and Horvitz, H.R. The C. elegans cell corpse engulfment gene ced-7 encodes a protein similar to ABC transporters. Cell, 93, 951-960 (1998).

3.       Wu, Y.C., Stanfield, G.M. and Horvitz, H.R. NUC-1, a Caenorhabditis elegans DNase II homolog, functions in an intermediate step of DNA degradation during apoptosis. Genes & Dev., 14, 536-548 (2000).

4.       Ledwich, D., Wu, Y.C. , Driscoll, M. and Xue, D., Analysis of programmed cell death in the nematode Caenorhabditis elegans. Methods in Enzymology , 322, 76-88(2000).

5.       Wu, Y.C. *, Tsai, M.C., Cheng L.C., Chou, C.C. and Weng N.Y., C. elegans CED-12 acts in the conserved CrkII/DOCK180/Rac pathway to control cell migration and cell-corpse engulfment. Dev. Cell, 1, 491-502 (2001). *corresponding author [This paper was the subject of a Preview by Barbara Conradt on Cell Engulfment, No Sooner ced Than Done, Dev. Cell 1, 1-20 (2001)]

6.       Wu, Y.C. *, Cheng, T.W., Lee, M.C. and Weng, N.Y. Distinct Rac activation pathways control C. elegans cell migration and axon outgrowth. Dev. Biol., 250, 145-155 (2002). * corresponding author

7.       Wang, X. # , Wu, Y.C. # *, Fadok, V., Lee, M., Gengyo-Ando, K., Cheng, L., Ledwich, D., Hsu, P., Chen, J., Chou, B., Henson, P., Mitani, S. and Xue, D.* Cell Corpse Engulfment Mediated by C. elegans Phosphatidylserine Receptor Through CED-5 and CED-12. Science 302,1563-1566 (2003) #These authors contributed equally to this work. * corresponding author [This paper was the subject of a Perspective by John Savil, Chris Gregory and Chris Haslet on Eat Me or Die, Science 302, 1516-1527 (2003)]

8.       deBakker, C.D., Haney, L.B., Kinchen, J. M., Grimsley, C., Lu,M., Klingele, D., Hsu, P.K., Chou, B.K., Cheng, L.C., Blangy, A., Sondek, J., Hengartner, M.O., Wu, Y.C. and Ravichandran, K.S. Phagocytosis of apoptotic cells is regulated by a UNC-73/TRIO ─ MIG-2/RhoG signaling module and Armadillo repeats of CED-12/ELMO. Curr. Biol. 14, 2208-2216(2004) [ This paper was the subject of a Dispatch by Peter Henson on Engulfment: Ingestion and Migration with Rac, Rho and TRIO, Curr. Biol., R29-30 (2004) ]

9.       Liu, W.H., Lin, Y.L., Wang, J.P., Liou, W., Hou, R.F., Wu, Y.C.* and Liao, C.L.* Restriction of Vaccinia Virus Replication by a ced-3 and ced-4 -Dependent Pathway in C. elegans. Proc. Natl. Acad. Sci. USA. 103, 4174-4179 (2006). *corresponding authors [ This paper was the subject of a Commentary by Shai Shaham on Worming into the cell: viral reproduction in Caenorhabditis elegans, PNAS (2006) 103, 3955–3956 ]

10.    Chen, K.Y., Pan, H., Lin, M.J., Li, Y.Y., Wang, L.C., Wu, Y.C., Hsiao, K.M. Length-dependent toxicity of untranslated CUG repeats on Caenorhabditis elegans. Biochem. Biophys. Res. Commun. 352, 774-977 (2007).

11.    Wang, L.C., Hung, W.T., Pan H., Chen, K.Y., Wu, Y.C., Liu Y.F., Hsiao K.M., Growth-dependent effect of muscleblind knockdown on Caenorhabditis elegans. Biochem. Biophys. Res. Commun. 366, 705-709 (2008).

12.    Lin, Y.M., Chen, Y.R., Lin, J.R., Wang, W.J., Inoko A., Inagaki, M., Wu, Y.C. , Chen R.H., eIF3k regulates apoptosis in epithelial cells by releasing caspase 3 from keratin-containing inclusions. J. Cell Sci. 121:2382-2393 (2008).

13.    Tong, A., Lynn, G., Ngo, V, Wong, D., Moseley, S.L., Ewbank J.J., Goncharov, A., Wu, Y.C., Pujol, N., and Chisholm, A.D., Negative regulation of Caenorhabditis elegans epidermal damage responses by death-associated protein kinase. Proc. Natl. Acad. Sci. USA. 106:1457-1461 (2009).

14.    Yeh, C.H., Yang, H. J., Lee, I. J. and Wu, Y.C.* C. elegans TLK-1 controls cytokinesis by localizing AIR-2/Aurora B to midzone microtubules. Biochem. Biophys. Res. Commun. 400, 187-193 (2010). * corresponding author

15.    Hsu, T. and Wu, Y.C.* Engulfment of apoptotic cells in C. elegans is mediated by integrin alpha/SRC signaling, Curr. Biol. 20:477-486 (2010). *corresponding author [ This paper was the subject of a Dispatch by Veera D'mello and Raymond B. Birge on Apoptosis: conserved roles for integrins in clearance, Current Biology (2010) 20, R324-327 ]

16.    Huang, C.Y., Chen, J.Y., Wu, S.C., Tan, C.H., Tzeng, R.Y., Lu, P.J., Wu, Y.F., Chen, R.H.*, Wu, Y.C.* C. elegans EIF-3.K Promotes Programmed Cell Death through CED-3 Caspase PLoS ONE, 7, e336584 (2012). * corresponding authors

17.    Hsieh, H.H. # , Hsu, T.-Y. # , Jiang, H.S. Wu, Y.C.* Integrin a PAT-2/CDC-42 Signaling Is Required for Muscle-Mediated Clearance of Apoptotic Cells in Caenorhabditis elegans. PLoS Genet. 8(5): e1002663. (2012). # These authors contributed equally to this work. * corresponding author

18.    Wu, Y.C., Wang, X, Xue, D. Methods for studying programmed cell death in C. elegans. Methods Cell Biol. 107:295-320. Review (2012).

19.    Jiang, H.S. and Wu, Y.C.* LIN-3/EGF promotes the programmed cell death of specific cells in Caenorhabditis elegans by transcriptional activation of the pro-apoptotic gene egl-1. PLoS Genet. 10(8):e1004513 (2014). * corresponding author

20.    Huang, T.F., Cho, C.Y., Cheng, Y.T., Huang, J.W., Wu, Y.Z., Yeh, A.Y., Nishiwaki, K., Chang, S.C., Wu, Y.C.* BLMP-1/Blimp-1 regulates the spatiotemporal cell migration pattern in C. elegans. PLoS Genet. 10(6):e1004428 (2014). * corresponding author

21.    Lin, Y.H., Chen, Y.C., Kao, T.Y., Lin, Y.C., Hsu, T.E., Wu, Y.C., Ja, W.W., Brummel, T.J., Kapahi, P., Yuh, C.H., Yu, L.K., Lin, Z.H., You, R.J., Jhong, Y.T., Wang, H.D. Diacylglycerol lipase regulates lifespan and oxidative stress response by inversely modulating TOR signaling in Drosophila and C. elegans. Aging Cell. 13(4):755-764 (2014).

22.    Chepyala, S.R., Chen, Y.C., Yan, C.C., Lu, C.Y., Wu, Y.C.* and Hsu, C.P.* Noise propagation with interlinked feed-forward pathways. Sci. Rep. 6:23607. doi: 10.1038/srep23607 (2016). *corresponding authors

23.    Conradt B, Wu YC*, Xue D. Programmed Cell Death During Caenorhabditis elegans Development. Genetics. 2016 Aug;203(4):1533-62. doi: 10.1534/genetics.115.186247.

24.    Yeh HY, Lin SW, Wu YC, Chan NL, Chi P. Functional characterization of the meiosis-specific DNA double-strand break inducing factor SPO-11 from C. elegans. Sci. Rep. 2017 May 24;7(1):2370. doi: 10.1038/s41598-017-02641-z.

25.    Chiu H, Zou Y, Suzuki N, Hsieh YW, Chuang CF, Wu YC, Chang C. Engulfing cells promote neuronal regeneration and remove neuronal debris through distinct biochemical functions of CED-1. Nat Commun. 2018 Nov 19;9(1):4842. doi: 10.1038/s41467-018-07291-x.

II. Application of Nanomaterials in Biology

1.       Lin, C.C.*, Yeh, Y.C., Yang, C.Y, Chen, C.L., Chen, G.F., Chen, C.C.*, Wu, Y.C.* Selective binding of mannose encapsulated gold nanoparticles to type 1 pili in Escherichia coli. J. Am. Chem. Soc., 124, 3508-3509 (2002). * corresponding authors

2.       Lin, C.C., Yeh, Y.C., Chen, G., Yang, C., Chen, Y., Wu, Y.C. and Chen, C.C. Quantitative Analysis of Multivalent Interactions of Carbohydrate Encapsulated Gold Nanoparticles with Concanavalin Chem. Com. 23, 2920-2921 (2003).

3.       Chen, C. C.,* Liu, Y.C., Wu, C.H., Yeh, C.C., Su, M.T. and Wu, Y.C.* Preparation of Fluorescent Silica Nanotubes and their Application in Gene Delivery. Adv. Mater . 17, 404-407 (2005) *corresponding author

4.       Chen,C.C., * Lin,I.P., Tzeng, S.C., Wang, J.W., Wu, C.H., Chen, Y.C., Chen, J.P., Chen, K.H., Su, M.T. and Wu, Y.C. * DNA-Gold Nanorod Conjugates for Remote Control of Localized Gene Expression by Near Infrared Irradiation. J. Am. Chem. Soc. 128, 3709-3715 (2006). *corresponding author

5.       Mohan, N., Chen, C.S., Hsieh, H.H., Wu, Y.C.* and Chang, H.C.* In vivo imaging and toxicity assessments of fluorescent nanodiamonds in Caenorhabditis elegans. Nano Lett. 10:3692-3699 (2010) *corresponding author [ This paper was the subject of Discovery news and PhysOrg.com. 

http://news.discovery.com/tech/nano-diamonds-diagnose-swallow.html 

http://www.physorg.com/news203230792.html ]

6.       Liu, Y. H., Tsai, Y. Y. 1, Chien, H. J., Chen. C. Y., Huang, Y. F., Chen, J. S., Wu, Y.C.* and Chen, C. C.* Quantum-dot-embedded silica nanotubes as nanoprobes for simple and sensitive DNA detection. Nanotechnology 22:155102-155107 (2011). *corresponding authors

7.       Kuo, Y., Hsu, T.Y., Wu, Y.C. *, Chang, H.C.* Fluorescent nanodiamond as a probe for the intercellular transport of proteins in vivo. Biomaterials 34(33):8352-8360 (2013). *corresponding authors

8.       Li, C.H., Kuo, T.R., Su, H.J., Lai, W.Y. , Yang, P.C., Chen, J.S. , Wang, D.Y. , Wu, Y.C.* and Chen, C.C.* Fluorescence-Guided Probes of Aptamer-Targeted Gold Nanoparticles with Computed Tomography Imaging Accesses for in Vivo Tumor Resection. Sci. Rep., 5:15675 | DOI: 10.1038/srep15675 (2015) *corresponding authors 

B. BOOKS AND BOOK CHAPTERS 

1.    Xue, D., Wu, Y.C., and Shah, M.M. (2002) Programmed cell death in C. elegans : the genetic framework. Apoptosis. The Molecular biology of Programmed Cell Death: Frontiers in Molecular Biology, M. Jacobson and N. McCarthy, ed. Oxford University Press. 

2.    Wu, Y.C., and Xue, D. (2003) Programmed cell death in C. elegans . Essentials of apoptosis: Guide for Basic and Clinical Research. The Humanna Press Inc. 

3.    Wu, Y.C., Wang, X. and Xue, D. Methods for Studying Programmed Cell Death in C. elegans . CAENORHABDITIS ELEGANS : CELL BIOLOGY AND PHYSIOLOGY, SECOND EDITION, J. Rothman and A. Singson, ed. Academic Press. 107, 297-320 (2012).

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