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      昆明理工大學

      昆明理工大學擬提名2019年度國家科學技術獎候選項目公示

      發布時間:2019-01-11  |   訪問量: 返回首頁

       

      為做好2019年度國家科學技術獎勵推薦工作,根據提名國家科學技術獎勵工作相關文件要求,為完善科技獎勵的社會監督工作,確保提名科技成果獎勵的公正性,現對以下項目的項目名稱、提名者及提名意見、項目簡介、客觀評價、代表性論文專著目錄、主要完成人情況、完成人合作關系說明等內容進行公示,公示期8天。在公示期間任何對公示內容有異議的單位或個人,請在公示期內實名并提供書面材料向科技處反映。

      公示時間:2019111日-2019118

      聯系電話:0871-65916002

      聯系人:科技處成果與綜合管理辦公室  李老師

       

      一、項目名稱:非人靈長類基因編輯與干細胞研究

       

      二、提名者及提名意見:

      提名者:云南省人民政府

      提名意見:擬提名國家自然科學獎二等獎

       

      三、項目簡介:

      干細胞和基因編輯是本世紀最重要的成果,使生命科學的理論和技術發生重大的改變,促進了對復雜疾病新的治療方法,以及生物醫藥產業發展的根本性變革。然而基于嚙齒類為模型的藥物研發體系最終實現臨床轉化的效率極低。靈長類動物與人類在基因組、腦結構與功能、生殖生理等方面具有高度的相似性,被認為是人類疾病研究、相關技術產品開發,特別是干細胞和基因編輯安全性和有效性評價最理想的實驗動物。利用靈長類動物模型開展人類疾病的發病機理研究、探索有效的預防及治療辦法,是基礎研究成果實現臨床轉化的重要橋梁。

      項目長期堅持靈長類生殖生物學研究,在相關科技專項支持下,圍繞早期胚胎發育調控、干細胞多能性和人類疾病靈長類動物模型建立等基礎和應用的科學問題,歷時15年,發現如下:

      1)系統地研究了靈長類動物生殖生理和早期胚胎發育相關科學問題,克服了猴輔助生殖技術的關鍵障礙,建立了高效靈長類動物的輔助生殖體系和闡明早期胚胎發育的調控機制,克服了靈長類體細胞核移植的瓶頸,首次實現猴體細胞克隆胚胎發育至囊胚,糾正了美國科學家以前認為靈長類克隆胚胎發育無法超過8細胞的錯誤結論;2)最早在我國開展靈長類干細胞的研究,率先建立了靈長類胚胎干細胞分離、培養和分化體系,建立了猴胚胎干細胞系的資源庫,在全世界首次獲得嵌合體猴,證明了猴干細胞的多能性即嵌合能力,為系統研究靈長類胚胎干細胞多能性及組織器官再生提供了堅實基礎。3)在靈長類實驗動物上開拓了基因工程技術以及應用,成功產生了我國首例、全球第三例轉基因獼猴;在國際上首次創制了基因編輯靈長類動物疾病模型,并開展了相關致病機理的研究。

      項目研究成果在CellCell Stem CellCell ResearchPNASStem CellsBiology of Reproduction等領域內的頂級期刊發表論文70多篇,總影響因子342.284,引用次數3192。其中8篇代表性研究論文的累計影響因子123.931,被包括CellNatureScience等他引637次,并多次被NatureScience等雜志正面評述。先后獲得云南省科技成果獎(自然科學類)二等獎1項,中國細胞生物學會終身成就獎1項,云南省科學技術獎(自然科學類)一等獎1項。靈長類基因編輯的成果入選2014年的《Nature》雜志最成功研究事件之一,《Cell》雜志最好的10篇研究論文,《MIT Technology Review2014年世界十大科技進展,以及云南省2014年十大科技進展;嵌合體猴的成果入選云南省2015年十大科技進展。基于本項目研究成果,《Nature》雜志2016年評價我國已是靈長類動物模型研究的猴王國。表明我國已進入逐漸成為全球靈長類研究的先進行列動物模型研究領域的領導者,對充分利用我國在靈長類動物的資源和技術基因編輯與干細胞的優勢,進一步開展重大基礎理論和原創技術的創新,加速我國新藥研發的進程、利用新技術對人類復雜疾病開展新的生物技術治療,以及推動人類醫藥和健康產業研究的發展意義重大。

       

      四、客觀評價:

      該項目針對靈長類生殖發育的關鍵科學問題展了系統的研究,在非人靈長類基因編輯與干細胞方面取得了一系列具有重要國際影響力的研究成果,發表了70多篇重要研究論文,被引用次數超過3192次,其中8篇代表性研究論文發表在CellCell Stem Cell等頂級期刊,被CellNatureScience等雜志引用637次,引起了國內外學術界的廣泛關注和高度評價。

      1.      靈長類體外生殖體系優化和胚胎發育機理新發現

      該項目較早開展靈長類胚胎發育的內在機制研究,發表SCI論文30余篇,他引超過1000次。為了弄清影響體細胞核移植胚胎的發育潛能及影響因素,2006年首次報道了靈長類體細胞核移植胚胎與體外受精胚胎著床前發育時期表觀遺傳水平的差異,闡述了靈長類動物克隆障礙的原因(Biol.Reprod.2006)。該文章是較早關于甲基化在胚胎發育過程中作用的研究,成為該雜志當年高引用文章之一。

      2.      靈長類干細胞的分離、培養和應用體系的優化以及干細胞多能性的新發現

      圍繞靈長類干細胞發表SCI論文20余篇,被引用400余次。2015年,首次證明利用靈長類胚胎干細胞獲得嵌合體猴(Cell Stem Cell2015)。證明猴體內發育多能干細胞的存在,為建立靈長類(含人)多能干細胞的鑒定標準和理解干細胞多能性提供了研究材料和技術平臺,為組織器官的體內再生提供了重要的研究基礎。同行專家評價為:“該工作不僅建立一套系統評估猴干細胞多能性的體系,而且為干細胞應用奠定了基石”(Stem Cell Investig2016)。該研究成果被評為云南省2015年十大科技成果。國際著名多能性干細胞專家以色列Weizmann 研究所的Jacob H HannaNat Rev Mol Cell BiolCurr Opin Genet Dev2015)評價了該工作的重要性,認為該成果在非人靈長類為干細胞發育多能性提供了一個最終證據(an ultimate proof)。

      3.      靈長類基因編輯疾病模型體系的創建及應用

      2010年,該項目報道了中國首例表達GFP蛋白的轉基因獼猴(PNAS2010)。這是繼美國和日本后,全球第三例轉基因靈長類動物的成功報道,使中國成為掌握此技術的全球第三個國家,開辟了我國靈長類基因工程研究的先河,為建立基因編輯靈長類動物模型奠定了基礎。論文發表后,《Science Daily》進行了專門報道,中央電視臺對研究工作進行了專題報道。

      2014年,該項目首次將CRISPR/Cas9基因靶向編輯技術應用于靈長類動物,實現了靈長類基因組的靶向編輯(Cell2014)。證明靈長類動物不僅可以實現基因的定點突變,還可以同時進行多基因突變,并實現了對生殖細胞的體內編輯(Cell Res2015)。《Nature》將這一工作稱為“人類疾病動物模型研究的里程碑”,并評為2014年成功科學事件之一。研究工作被麻省理工大學的《MIT Technology Review》評為2014年全球十大科技進展和云南省2014年十大科技進展。研究論文不僅入選《Cell》雜志2014年最受關注十篇論文之一,同時也高居該雜志迄今為止關注度前5%文章,發表以來已被引用440次。同年,該也通過TALEN體系首次實現了食蟹猴和獼猴基因組的編輯(Cell Stem Cell2014),目前已被引用98次。這些工作奠定了我國在靈長類基因編輯在全球的領先地位。后續的模型研究中進一步基因編輯猴模型表現出與人類臨床癥狀高度相似的表型,對疾病致病機理的研究意義重大,《Science Translational Medicine》雜志認為“猴子提供了一個很好的機會進行時間縱向研究,評估大腦結構隨時間的變化,而這項任務在嚙齒動物上很難完成。”

          項目的系列研究成果,為我國在靈長類的研究躋身于世界先進行列發揮了重要作用。2016Nature雜志以猴王國:中國在靈長類研究領域正在置身全球領導地位(MONKEY KINGDOM: China is positioning itself as a world leader in primate research為題評論為:中國在靈長類實驗動物的研究和設施建設呈現出快速發展的態勢,在全球靈長類研究中處于領導地位。該報道重點介紹了該項目的研究平臺,認為其平臺已迅速成為尖端靈長類動物研究的圣地,產生了許多有價值的疾病模型,發表了具有開創性的研究成果論文(Since it opened in 2011, this place has quickly become a Mecca for cutting-edge primate research, producing valuable disease models and seminal publications)。瑞典斯德哥爾摩Karolinska研究所國際頂尖的心臟病專家Kenneth Chien評價,就技術平臺而言,該團隊處于世界領先水平。其團隊成員季維智研究員由于在靈長類動物生物醫學上的突出成績,被選為世界經濟論壇全球未來理事會理事(2016-2018)。


      五、代表性論文專著目錄(不超過8篇)

      序號

      論文專著

      名稱/刊名

      /作者

      年卷頁碼

      xxxx

      xx頁)

      發表時間(年月日)

      通訊作者(含共同)

      第一作者(含共同)

      國內作者

      SCI

      他引次數

      他引總次數

      論文署名單位是否包含國外單位

      1

      Effect of age and breeding season on the developmental capacity of oocytes from unstimulated and Follicle-stimulating hormone stimulated rhesus monkeys/Biol. Reprod.

      2001, 64(5): 1417-1421.

      2001 May

      季維智

      鄭萍、

      司維

      5

      18

      18

      包含

      2

      Epigenetic marks in cloned rhesus monkey embryos: comparison with counterparts produced in vitro/Biol. Reprod.

      2007, 76(1): 36-42.

      2007 Jan

      周琪、季維智

      楊紀峰

      9

      48

      48

      3

      Transgenic rhesus monkeys produced by gene transfer into early cleavage stage embryos using a simian immunodeficiency virus-based vector/Proc Natl Acad Sci U S A.

      2010, 107(41): 17663-17667.

      2010 Oct 12

      周琪、季維智

      牛昱宇、于洋、Agnieszka Bernat

      18

      21

      21

      包含

      4

      Generation of Gene-Modified Cynomolgus Monkey via Cas9/RNA-Mediated Gene Targeting in One-Cell Embryos/Cell

      2015, 156(4): 836-843.

      2014 Feb 13

      黃行許、季維智、沙家豪

      牛昱宇、沈彬、崔益強、陳永昌

      28

      412

      412

      5

      Generation of Cynomolgus Monkey Chimeric Fetuses using Embryonic Stem Cells/ Cell Stem Cell

      2015, 17(1): 116-124

      2015 Jul 2

      李天晴、季維智

      陳永昌、牛昱宇

      15

      40

      40

      6

      TALEN-Mediated Gene Mutagenesis in Rhesus and Cynomolgus Monkeys/Cell Stem Cell

      2014, 14(3): 323-328.

      2014 Mar 6

      李思光、孫毅、季維智

      劉海亮、陳永昌、牛昱宇、張坤山

      32

      86

      86

      7

      Generation of cardiac spheres from primate pluripotent stem cells in a small molecule-based 3D system/Biomaterials

      2015, 65: 103-14.

      2015 Oct

      蔣斌

      季維智、李天晴

      7

      4

      4

      8

      Germline acquisition of Cas9/RNA-mediated gene modifications in monkeys/Cell Res

      2015, 25(2): 262-265.

      2015 Feb

      季維智、沙家豪、黃行許

      陳永昌、崔益強、沈彬、牛昱宇

      12

      8

      8

       

      637

      637

       

      六、代表性論文專著被他人引用的情況(不超過8篇)

      序號

      被引代表性論文專著序號

      引文名稱/作者

      引文刊名

      引文發表時間

      (年日)

      1

      2

      Producing primate embryonic stem cells by somatic cell nuclear transfer/Byrne JA, Pedersen DA, Clepper LL, Nelson M, Sanger WG, Gokhale S, Wolf DP, Mitalipov SM

      Nature

      20071122

      2

      3

      SIRT6 deficiency results in developmental retardation cynomolgus monkeys/Zhang W, Wan H, Feng G, Qu J, Wang J, Jing Y, Ren R, Liu Z, Zhang L, Chen Z, Wang S, Zhao Y, Wang Z, Yuan Y, Zhou Q, Li W, Liu GH, Hu B

      Nature

      20180830

      3

      3

      Brains, genes, and primates/Izpisua Belmonte JC, Callaway EM, Caddick SJ, Churchland P, Feng G, Homanics GE, Lee KF, Leopold DA, Miller CT, Mitchell JF, Mitalipov S, Moutri AR, Movshon JA, Okano H, Reynolds JH, Ringach D, Sejnowski TJ, Silva AC, Strick PL, Wu J, Zhang F

      Neuron

      2015 0506

      4

      4

      From the RNA world to the clinic/Sullenger BA, Nair S

      Science

      20160617

      5

      4

      Cloning of Macaque Monkeys by Somatic Cell Nuclear Transfer/ Liu Z, Cai Y, Wang Y, Nie Y, Zhang C, Xu Y, Zhang X, Lu Y, Wang Z, Poo M, Sun Q

      Cell

      20180628

      6

      5

      Stem cells and interspecies chimaeras/ Wu J, Greely HT, Jaenisch R, Nakauchi H, Rossant J, Belmonte JC

      Nature

      20181201

      7

      6

      Autism-like behaviours and germline transmission in transgenic monkeys overexpressing MeCP2/Liu Z, Li X, Zhang JT, Cai YJ, Cheng TL, Cheng C, Wang Y, Zhang CC, Nie YH, Chen ZF, Bian WJ, Zhang L, Xiao J, Lu B, Zhang YF, Zhang XD, Sang X, Wu JJ, Xu X, Xiong ZQ, Zhang F, Yu X, Gong N, Zhou WH, Sun Q, Qiu Z

      Nature

      20160204

      8

      8

      Generation of knock-in cynomolgus monkey via CRISPR/Cas9 editing/Yao X, Liu Z, Wang X, Wang Y, Nie YH, Lai L, Sun R, Shi L, Sun Q, Yang H

      Cell Res

      20180328

       

      七、主要完成人情況

         

      季維智

      性別

         

      第一

         

      中國

      技術職稱

      研究員

      行政職務

      院長

      工作單位

      昆明理工大學

      完成單位

      昆明理工大學

      對本項目主要學術貢獻:

      項目負責人,在國內較早開展靈長類動物生殖與發育生物學研究,系統地掌握了靈長類動物生殖生理,并建立了超排、體外受精及胚胎體外培養體系,并系統地研究了靈長類動物早期胚胎發育及體細胞核移植過程中的分子事件;建立了靈長類胚胎干細胞系,并分化為神經、心肌及肝前體細胞;建立了國內首例轉基因猴,率先將基因編輯成功應用于靈長類動物上,并獲得一系列發育代謝疾病的靈長類動物模型,為深入開展發病機制及治療研究奠定了基礎。對發現點123具有重要貢獻,代表性論文1-8,附件1-17。培養了一批優秀的學術骨干;創建了昆明理工大學靈長類轉化醫學研究院,是本項目實施的重要平臺和基礎。

       

         

      牛昱宇

      性別

         

      第二

         

      中國

      技術職稱

      教授

      行政職務

      院長

      工作單位

      昆明理工大學

      完成單位

      昆明理工大學

      對本項目主要學術貢獻:

      項目骨干,參與靈長類生殖發育、體細胞核移植胚胎發育阻滯機理研究;主持完成了國內首例轉基因猴的構建;主持了世界首例基因編輯猴的構建,以第一作者在Cell雜志發表CRISPR/Cas9基因編輯猴的文章,并在此基礎上建立了多種疾病的猴模型;主持了多項973計劃、863計劃、國家自然科學基金項目。對發現點23具有重要貢獻,代表性論文3,5-8,附件1-1316

       

         

      李天晴

      性別

         

      第三

         

      中國

      技術職稱

      教授

      行政職務

      工作單位

      昆明理工大學

      完成單位

      昆明理工大學

      對本項目主要學術貢獻:

      2002年開始從事靈長類干細胞的分離、培養和應用體系的優化以及干細胞多能性的研究。作為通訊作者與季維智、陳永昌和牛昱宇合作建立了嵌合體猴,與季維智合作建立了多能干細胞、心肌細胞的三維培養及分化體系。本人對這兩篇論文起到了關鍵性的貢獻,啟動了這兩個項目,負責實驗的設計、部分實驗的開展、實驗結果的收集以及實驗數據的分析,撰寫了該兩篇論文,組織和監督這兩個項目的順利完成。對發現點2具有重要貢獻,代表性論文34,附件6-7

       

         

      陳永昌

      性別

         

      第四

         

      中國

      技術職稱

      教授

      行政職務

      工作單位

      昆明理工大學

      完成單位

      昆明理工大學

      對本項目主要學術貢獻:

      項目骨干,參與靈長類動物生殖及發育生物學研究,并建立了高效穩定的靈長類基因工程研究平臺。參與構建了中國第一例轉基因獼猴;作為共同第一作者獲得了世界第一例CRISPR/Cas9及第一例TALEN基因編輯猴,獲得第一只基因編輯的瑞特綜合征猴模型,以及帕金森病、杜氏肌營養不良癥等猴模型;合作制作了第一例胚胎干細胞嵌合體猴;通過單細胞測序對基因編輯猴的生殖細胞進行了遺傳學分析,證明實現了生殖腺基因編輯。對發現點23具有重要貢獻,代表性論文36-8,附件1-1012-1316

       

         

      沙家豪

      性別

         

      第五

         

      中國

      技術職稱

      教授

      行政職務

      實驗室主任

      工作單位

      南京醫科大學

      完成單位

      南京醫科大學

      對本項目主要學術貢獻:

      與季維智團隊合作構建了世界首例CRISPR/Cas9基因編輯食蟹猴,并證明實現了生殖腺編輯,為利用基因編輯建立疾病的靈長類動物模型奠定了基礎。對發現點3具有重要貢獻,代表性論文68,附件1-5

       

      八、完成人合作關系說明

      完成人及排序為:季維智(第一)、牛昱宇(第二)、李天晴(第三)、陳永昌(第四)、沙家豪(第五)。

      牛昱宇與季維智合作完成了國內第一例轉基因猴的研究工作,發表了代表論文3,牛昱宇為第一作者,季維智為通訊作者;

      牛昱宇與陳永昌、季維智、沙家豪合作完成了世界首例CRISPR/Cas9基因編輯猴的工作,發表了代表論文4,牛昱宇、陳永昌為第一作者,季維智和沙家豪為通訊作者;

      李天晴與陳永昌、牛昱宇、季維智合作構建了世界首例胚胎干細胞嵌合體猴,發表了代表論5,陳永昌和牛昱宇為第一作者,季維智和李天晴為通訊作者;

      李天晴與季維智合作建立了心肌細胞體外分化及培養的三維體系;

      陳永昌與牛昱宇、季維智等合作建立了世界首例TALEN基因編輯猴的研究工作,發表了代表論文6,陳永昌和牛昱宇為第一作者,季維智為通訊作者;

      陳永昌與季維智、沙家豪合作,分析了基因編輯猴的生殖細胞,證明基因編輯具有生殖腺傳遞的能力,發表了代表論文8,陳永昌為第一作者,季維智和沙家豪為通訊作者;

      季維智團隊對獼猴生殖生理及卵泡發育規律進行了系統研究,發表了代表論文1,季維智為通訊作者;

      季維智團隊對體細胞核移植胚胎發育過程中的表觀調控因素進行了分析,發表了代表論文2,季維智為通訊作者。

       

       

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