克里斯蒂安·布雷紹
克里斯蒂安·布雷肖(Christian Bréchot,1952年7月23日出生)是一位法國醫師暨科學家,自2017年起擔任全球病毒網絡(GVN)主席。他曾於2013年至2017年擔任巴斯德研究院院長,並於2001年至2007年擔任法國國家健康與醫學研究院(INSERM)執行長。
職業生涯
布雷肖專精於B型和C型肝炎以及肝癌背後的機制。他於1993年被任命為INSERM肝癌與分子病毒學單位(U370)主任,並於1998年擔任法國國家病毒性肝炎參考中心負責人。1997年,他成為內克爾兒童醫院肝病學系主任,任職至2001年。他也曾負責內克爾醫學院細胞生物學系,直至2001年。
2001年2月14日,布雷肖接替克勞德·格里切利成為INSERM執行長。2008年至2013年,克里斯蒂安·布雷肖擔任馬里埃研究院醫學與科學事務副總裁,該研究院是一家傘形組織,由四家專精於體外診斷、免疫療法及食品安全/營養/健康領域的公司組成,總部分別設於波士頓、里昂和上海。他為醫師和科學家設立了一項培訓與研究計畫—馬里埃研究獎助金網絡—為創新研究計畫提供大規模且靈活的資金支持。這使他得以發展出一個由著名研究人員和科學家組成的國際網絡,尤其是在亞洲和南美洲。他也參與了開發中和新興國家的培訓與教育活動。他在醫學和純科學領域開發了多項培訓計畫(作為「INSERM學院」的一部分)。他設立了「INSERM未來計畫」獎助金,以幫助年輕科學家發展獨立的研究計畫。
2013年3月8日,巴斯德研究院宣布布雷肖獲任命為院長,任期四年,自2013年10月1日起生效,接替愛麗絲·多特里。巴斯德研究院董事會於2017年1月24日宣布,克里斯蒂安·布雷肖將於2017年9月30日四年任期屆滿後卸任。
自上任以來,布雷肖的目標一直是維持研究院的卓越聲望,並發展其國際影響力:「我們必須讓自己有能力重新創造一個科學且具吸引力的環境,以吸引傑出的研究人員,並應對新的公共衛生挑戰」(《世界報》)。
研究
布雷肖的研究主要聚焦於病毒性B型肝炎(HBV)和C型肝炎(HCV),特別是它們與肝癌(肝細胞癌,HCC)的關聯,以及支撐肝臟再生與癌症(特別是細胞週期的失調)的分子機制。他的工作結合了分子病毒學和細胞生物學的學術與臨床方法。
布雷肖的研究著重於B型肝炎病毒DNA整合的影響,以及C型肝炎病毒蛋白質與主要細胞信號傳導路徑(如干擾素和TGF-β路徑)之間的交互作用,有助於增進對慢性B型或C型肝炎感染患者肝癌機制的理解。克里斯蒂安·布雷肖的研究團隊也闡明了與細胞週期調控相關的幾個方面,特別是透過在一個肝細胞癌的B型肝炎病毒基因組插入位點鑑定了人類細胞週期蛋白A。
布雷肖指導了數個計畫,促成了一種用於檢測和定量血清中B型肝炎病毒DNA的創新診斷測試的開發。他的團隊還利用雷射顯微切割技術對肝臟切片進行C型肝炎病毒RNA檢測、C型肝炎病毒準種分析以及肝臟蛋白質體學分析。克里斯蒂安·布雷肖研究了C型肝炎病毒遺傳變異性的臨床影響,他的臨床試驗證明了干擾素-利巴韋林合併療法在治療C型肝炎病毒感染方面的療效。
2005年,布雷肖在巴黎郊區維勒瑞夫的肝膽中心(CHB)設立了一個單位(由迪迪埃·薩繆爾教授指導),該中心是歐洲主要的肝臟移植中心之一。該團隊探索了HIP/PAP分子的潛力,該分子在肝細胞中具有促有絲分裂和抗細胞凋亡的特性,並證明HIP/PAP具有一個非常獨創的作用機制:其內源性活性氧及抗氧化路徑阻斷特性特別針對細胞外基質。
科學家們還證明了基於使用NIS dnaC轉導肝癌細胞的基因治療潛力,以及使用碘化物(131I)治療肝細胞癌的潛力。
其他活動
- 流行病預防創新聯盟(CEPI),科學顧問委員會成員
獎項與榮譽
布雷肖是數個法國及國際專業醫學協會的成員。他曾獲得多個獎項,包括1996年的法國國家醫學科學院獎和2000年的尚-瓦拉德獎。他亦於1991年成為法國大學研究院的初級成員,為期五年。
論文
- Brechot, C., Pourcel, C., Louise, A., Rain B., and Tiollais P. Presence of integrated hepatitis B virus DNA sequences in cellular DNA of human hepatocellular carcinoma. Nature, 1980, 286, 533–535.
- Brechot, C., Hadchouel, M., Degos, F. Lugassy, C., Thiers, V., Zafrani, S., Franco, D., Bismuth, H., Trepo, C., Benhamau, J.P., Wands, J., Isselbacher, K., Tiollais P., and Berthelot, P. Hepatitis B virus DNA in patients with chronic liver disease and negative tests for hepatitis B surface antigen. N. Engl. J. Med., 1985, 312, 270- 276.
- Wang, J., Chenivesse, X., Heinglein, B., and Brechot, C. Hepatitis B virus integration in a cyclin A gene in hepatocellular carcinoma. Nature, 1990, 343, 557-557.
- Murphy, M., Stinnakre, M.G., Senamaud-Beaufort, C., Sweeney, C., Kubelka, M., Carrington, M., Brechot, C., and Sobczak-Thepot, J. Delayed early embryonic lethality following disruption of the murine cyclin A2 gene. Nature Genetics. 1997, 15: 83–86.
- Barba, G., Harper, F., Harada, T., Kohara, M., GOULINET, S., Matsuura, Y., Eder, G., Schaff, Z.S., Chapman, M.J., Miyamura, T., and Brechot, C. Hepatitis C virus core protein shows an exclusively cytoplasmic localization and associates to cellular lipid storage droplets. The Proceeding National Academy of Sciences USA. 1997, 94: 1200–1205.
- Soussan, P., Garreau, F., Zylberberg, H., Ferray, C., Brechot, C., and Kremsdorf, D. In vivo expression of a new hepatitis B virus protein encoded by a spliced RNA. Journal of Clinical Investigation. 2000. 105(1): 55–60.
- Fontaine, H., Chaix, M-L., Lagneau, J-L., Brechot, C., Pol, S and a French multicentric study group. Recovery from chronic hepatitis C in long-term responders to ribavirin plus interferon-alpha. Lancet, 2000; 356: 41.
- Gordien, E., Rosmorduc, O., Peltekian, C., Garreau, F., Brechot, C., and Kremsdorf, D. Inhibition of hepatitis B virus replication by the interferon-inducible MxA protein. Journal of Virology, 2001; 75:2684.
- Perlemuter, G., Sabile, A., Letteron, P., Vona, G., Topilco, A., Samson-Bouma, M.E., Chretien, Y., Pessayre, D., Koike, K., Chapman, J., Barba, G., Brechot, C. Hepatitis C virus core protein inhibits microsomal triglyceride transfer protein activity and very low density lipoprotein secretion:a model of viral-related steatosis. FASEB Journal. 2002, 16:185-194.
- Tralhao, G., Roudie, J., Morosan, S., Giannini, G., C., Tu, H., Goulenok, C., Carnot, F., Zavala, F., Joulin, V., Kremsdorf, D., Brechot, C. Paracrine in vivo inhibitory effects of hepatitis B virus X (HBx) protein on liver cell proliferation:a new mechanism of HBx-related pathogenesis. Proc. Natl. Acad Sci U S A. 2002 May 14; 99(10): 6991–6996. doi: 10.1073/pnas.092657699
- Simon, M.-T., Pauloin, A., Normand G., Lieu H.-T., Mouly H., Pivert G., Carnot F., Trailhao J.G., Brechot C. HIP/HAP stimulates liver generation after partial hepatectomy and combines mitogenic and anti-apoptotic functions through the PKA signaling pathway. Faseb J. 2003, 17(11): 1141–50.
- Faivre J, Clerc J, Gerolami R, Herve J, Longuet M, Liu B, Roux J, Moal F, Perricaudet M, Brechot C. Long-term radioiodine retention and regression of liver cancer after Sodium Iodide Symporter gene transfer in Wistar rats. Cancer Research. 2004. Nov 1;64 (21): 8045.51.
- Girard S, Vossman E, Misek D E, Podevin P, Hanash S, Brechot C, Beretta L. HCV NS5A-regulated gene expression and signaling revealed by microarray and comparative promoter analyses. Hepatology. 2004. Oct; 40(3) 708–18.
- Mancini-Bourgine M, Fontaine H, Scott-Algara D, Pol S, Brechot C, Michel ML. Induction or expansion of T-cell responses by a hepatitis B DNA vaccine administered to chronic HBV carriers. Hepatology, vol 40 (4) 874–882.
- Andre P., Perlemuter G., Budkowska A., Brechot C., Lotteau V. Hepatitis C virus particles and lipoprotein metabolism. Semin Liver Dis. 2005, Feb 25,(1):93-104.
- Murakami Y., Saigo K., Takashima H, Minami M., Okanoue T., Brechot C., Paterlini-Brechot P. Large scaled analysis of hepatitis B virus (HBV) DNA integration in HBV related hepatocellular carcinomas. Gut, 2005. Aug, 54(8):1162-8.
- Pavio N, Boucreux D, Battaglia S, Arnulf B, Sobesky R, Hermine O, Brechot C. Hepatitis C virus core variants isolated from liver tumor but not from adjacent non tumor interact with Smad3 and inhibit the TGF-beta signaling. Oncogene. 2005, Sept 8;24(40):6119-32.
- Lieu HT., Batteux F., Simon MT., Cortes A., Nicco C., Zavala F., Pauloin A., Tralhao JG., Soubrane O., Weill B., Brechot C., Christa L. HIP/PAP accelerates liver regeneration and protects against acetaminophen injury in mice. Hepatology, 2005 Sep, 42(3):618-26.
- Haeffner-Cavaillon N., Graillot-Gak C., Brechot C. Automated grading of research performance clearly fails to measure up. Nature, 2005, Dec 1, 438(7068):559.
- Lieu HT, Simon HT, Nguyen-Khoa T, Kebede M, Cortes A, Tebar L, Smith AJ, Bayne R, Hunt SP, Brechot C, Christa L. Reg2 inactivation increases sensitivity to Fas hepatotoxicity and delays liver regeneration post-hepatectomy in mice. Hepatology. 2006 Dec;44(6):1452-64.
- Liu B, Herve J, Bioulac-Sage P, Valogne Y, Roux J, Yilmaz F, Boisgard R, Guettier C, Cales P, Tavitian B, Samuel D, Clerc J, Brechot C and Faivre J; Sodium iodide symporter is expressed at the preneoplastic stages of liver carcinogenesis and in human cholangiocarcinoma.. Gastroenterology. 2007 Apr;132(4):1495-503. Epub 2007 Jan 26.
- Sobesky R, Feray C, Rimlinger F, Derian N, Dos Santos A, Roque-Afonso A-M, Samuel D, Brechot C and Thiers V. Distinct Hepatitis C Virus Core and F protein quasispecies in tumoral and nontumoral hepatocytes. Hepatology 2007 Dec;46(6):1704-12.
- Dos Santos A, Thiers V, Sar S, Derian N, Bensalem N, Yilmaz F, Bralet MP, Ducot B, Brechot C, Demaugre F.Contribution of laser microdissection-based technology to proteomic analysis in hepatocellular carcinoma developing on cirrhosis. Proteomics Clin Appl. 2007 Jun;1(6):545-54.
- Faria LC, Gigou M, Roque-Afonso AM, Sebagh M, Roche B, Fallot G, Ferrari TC, Guettier C, Dussaix E, Castaing D, Brechot C, Samuel D. Hepatocellular carcinoma is associated with an increased risk of hepatitis B virus recurrence after liver transplantation. Gastroenterology. 2008 Jun;134(7):1890-9; quiz 2155.
- Herve, J., Sa Cunha, A., Liu, B., Valogne, Y., Longuet, M., Boisgard, R., Bregerie, O., Roux, J., Guettier, C., Cales, P., Tavitian, B., Samuel, D., Clerc, J., Brechot, C., Faivre, J. Internal radiotherapy of liver cancer with rat Hepatocarcinoma-Intestine-Pancreas gene as a liver tumor-specific promoter. Hum Gene Hum Gene Ther. 2008 Sep; 19(9):915-26
- Battaglia S, Benzoubir N, Nobilet S, Charneau P, Samuel D, Zignego AL, Atfi A, Brechot C, Bourgeade MF
- Liver cancer-derived hepatitis C virus core proteins shift TGF-Beta responses from tumor suppression to epithelial-mesenchymal transition PLoS ONE. 2009;4(2):e4355.
- Dos Santos A, Court M, Thiers V, Sar S, Guettier C, Samuel D, Brechot C, Garin J, Demaugre F, Masselon CD. Identification of cellular targets in human intrahepatic cholangiocarcinoma using laser microdissection and accurate mass and time tag proteomics. Mol Cell Proteomics. 2010 Sep;9(9):1991-2004.
- Moniaux, N., Song, H., Darnaud, M., Garbin, K., Gigou, M., Mitchell, C., Samuel, D., Jamot, L., Amouyal, P., Amouyal, G., Brechot, C., Faivre, J. Human hepatocarcinoma-intestine-pancreas/pancreatitis-associated protein cures fas-induced acute liver failure in mice by attenuating free-radical damage in injured livers. Hepatology. 2011 Feb;53(2):618-27. doi: 10.1002/hep.24087
- Arumugam M, Raes J, Brechot C, Merieux A, Weissenbach J, Ehrlich SD, Bork P. Enterotypes of the human gut microbiome. Nature. 2011 May 12;473(7346):174-80.
- Claire Lacoste, Julie Hervé, Myriam Bou Nader, Alexandre Dos Santos, Nicolas Moniaux, Yannick Valogne, Rodrick Montjean, Olivier Dorseuil, Didier Samuel, Doris Cassio, Carla Portulano, Nancy Carrasco, Christian Bréchot, and Jamila Faivre. The iodide transporter NIS regulates cancer cell motility and invasiveness by interacting with the RhoGEF LARG. Cancer Research. 2012 Nov 1;72(21):5505-15
- N. Benzoubir, C. Lejamtel, B. Testoni, S. Battaglia, B. Benassi, C. Desterke, D. Samuel, M. Levrero4, C. Bréchot and MF Bourgeade. HCV core-mediated activation of latent TGF-β via thrombospondin drives the cross-talk between hepatocytes and stromal environment. J Hepatol. 2013 Dec;59(6):1160-8.