1）袁鈞瑛教授早期的學(xué)術(shù)貢獻(xiàn)是在麻省理工諾貝爾獎(jiǎng)獲得者H. Robert Horvitz教授實(shí)驗(yàn)室攻讀博士學(xué)位期間完成的。她利用線蟲首次揭示了程序性細(xì)胞死亡的分子機(jī)制，這項(xiàng)工作發(fā)現(xiàn)了生物有機(jī)體中第一個(gè)細(xì)胞凋亡（apoptosis）的調(diào)控機(jī)制。參考文獻(xiàn)如下：
a. Yuan JY, Horvitz HR. The Caenorhabditis elegans genes ced-3 and ced-4 act cell
autonomously to cause programmed cell death. Dev Biol. 1990 Mar;138(1):33-41. PMID: 2307287.
http://www.ncbi.nlm.nih.gov/pubmed/2307287
b. Yuan J, Horvitz HR. The Caenorhabditis elegans cell death gene ced-4 encodes a novel protein and is expressed during the period of extensive programmed cell death. Development.
1992 Oct;116(2):309-20. PMID: 1286611.
http://www.ncbi.nlm.nih.gov/pubmed/1286611
c. Yuan J, Shaham S, Ledoux S, Ellis HM, Horvitz HR. The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme. Cell. 1993. Nov 19;75(4):641-52. PMID: 8242740.
http://www.ncbi.nlm.nih.gov/pubmed/8242740
d. Yuan J, Horvitz HR. A first insight into the molecular mechanisms of apoptosis. Cell.
2004; 116(2 Suppl):S53-6, 1 p following S59. PMID: 15055582
https://www.ncbi.nlm.nih.gov/pubmed/?term=15055582
2）袁鈞瑛教授建立了自己的獨(dú)立實(shí)驗(yàn)室之后，其發(fā)表的前兩篇學(xué)術(shù)論文首次提供了半胱天冬酶（caspases）調(diào)控哺乳動(dòng)物細(xì)胞凋亡的證據(jù)。這項(xiàng)工作首次揭示了哺乳動(dòng)物細(xì)胞凋亡（apoptosis）的分子機(jī)制，引領(lǐng)了細(xì)胞死亡研究進(jìn)入分子水平的新時(shí)代。這些開創(chuàng)性發(fā)現(xiàn)引起了世界研究領(lǐng)域的巨大興趣，迄今為止，在這兩篇研究論文的基礎(chǔ)上已經(jīng)發(fā)表了超過十一萬四千多篇關(guān)于半胱天冬酶在哺乳動(dòng)物細(xì)胞凋亡中作用的學(xué)術(shù)論文。參考文獻(xiàn)如下：
a. Miura M, Zhu H, Rotello R, Hartwieg EA, Yuan J. Induction of apoptosis in fibroblasts by IL-1 beta-converting enzyme, a mammalian homolog of the C. elegans cell death gene ced-3. Cell. 1993 Nov 19;75(4):653-60. PMID: 8242741.
http://www.ncbi.nlm.nih.gov/pubmed/?term=8242741
b. Gagliardini V, Fernandez PA, Lee RK, Drexler HC, Rotello RJ, Fishman MC, Yuan J. Prevention of vertebrate neuronal death by the crmA gene. Science. 1994 Feb 11;263(5148):826-8. PubMed PMID: 8303301.
http://www.ncbi.nlm.nih.gov/pubmed/?term=8303301
3）袁鈞瑛教授實(shí)驗(yàn)室闡明了哺乳動(dòng)物細(xì)胞中caspase 家族的多個(gè)成員在調(diào)控細(xì)胞凋亡（apoptosis）信號(hào)轉(zhuǎn)導(dǎo)通路以及在神經(jīng)退行性疾病中的功能和參與的分子機(jī)制，其中包括揭示了被細(xì)胞膜死亡受體復(fù)合物激活的caspase-8 能夠剪切Bcl-2 家族的促凋亡成員Bid。 Bid的剪切對(duì)啟動(dòng)線粒體損傷和其他下游細(xì)胞凋亡機(jī)制中起到了關(guān)鍵的作用。參考文獻(xiàn)如下：
a. Wang L, Miura M, Bergeron L, Zhu H, Yuan J. Ich-1, an Ice/ced-3-related gene, encodes both positive and negative regulators of programmed cell death. Cell. 1994 Sep 9;78(5):739-50. PMID: 8087842.
http://www.ncbi.nlm.nih.gov/pubmed/?term=8087842
b. Li H, Zhu H, Xu CJ, Yuan J. Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell. 1998 Aug 21;94(4):491-501. PMID: 9727492.
http://www.ncbi.nlm.nih.gov/pubmed/?term=9727492
c. Sánchez I, Xu CJ, Juo P, Kakizaka A, Blenis J, Yuan J. Caspase-8 is required for cell death induced by expanded polyglutamine repeats. Neuron. 1999 Mar;22(3):623-33. PMID: 10197541.
http://www.ncbi.nlm.nih.gov/pubmed/?term=10197541
d. Nakagawa T, Zhu H, Morishima N, Li E, Xu J, Yankner BA, Yuan J. Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature. 2000 Jan 6;403(6765):98-103. PMID: 10638761.
http://www.ncbi.nlm.nih.gov/pubmed/?term=10638761
4）袁鈞瑛教授實(shí)驗(yàn)室首先發(fā)現(xiàn)了caspase-11，并闡明了caspase-11 通過激活caspase-1來調(diào)控炎癥以及通過激活caspase-3 調(diào)控細(xì)胞凋亡（apoptosis）的機(jī)理，還發(fā)現(xiàn)了其在非凋亡的條件下調(diào)控炎癥過程中細(xì)胞遷移的作用。近來的研究證明Caspase-11 是介導(dǎo)細(xì)胞焦亡的關(guān)鍵蛋白。參考文獻(xiàn)如下：
a. Wang S, Miura M, Jung YK, Zhu H, Li E, Yuan J. Murine caspase-11, an ICE interacting protease, is essential for the activation of ICE. Cell. 1998 Feb 20;92(4):501-9. PMID: 9491891.
http://www.ncbi.nlm.nih.gov/pubmed/?term=9491891
b. Kang SJ, Wang S, Hara H, Peterson EP, Namura S, Amin-Hanjani S, Huang Z, Srinivasan A, Tomaselli KJ, Thornberry NA, Moskowitz MA, Yuan J. Dual role of caspase-11 in mediating activation of caspase-1 and caspase-3 under pathological conditions. J Cell Biol. 2000 May 1;149(3):613-22. PMID: 10791975; PMCID:
PMC2174843
http://www.ncbi.nlm.nih.gov/pubmed/?term=10791975
c. Li J, Brieher WM, Scimone ML, Kang SJ, Zhu H, Yin H, von Andrian UH, Mitchison T, Yuan J. Caspase-11 regulates cell migration by promoting Aip1-Cofilin-mediated actin depolymerization. Nat Cell Biol. 2007 Mar;9(3):276-86. PMID: 17293856.
http://www.ncbi.nlm.nih.gov/pubmed/?term=17293856
d. Py BF, Jin M, Desai BN, Penumaka A, Zhu H, Kober M, Dietrich A, Lipinski MM, Henry T, Clapham DE, Yuan J. Caspase-11 controls interleukin-1β release through degradation of TRPC1. Cell Rep. 2014 Mar 27;6(6):1122-8. PMID: 24630989.
http://www.ncbi.nlm.nih.gov/pubmed/?term=24630989
5）袁鈞瑛教授實(shí)驗(yàn)室發(fā)現(xiàn)了一種新的由死亡受體介導(dǎo)的不依賴于caspase 的細(xì)胞壞死方式，并將其命名為程序性細(xì)胞壞死（necroptosis）。細(xì)胞壞死在傳統(tǒng)觀念中被認(rèn)為是細(xì)胞在巨大逆境下被動(dòng)的死亡方式，這種觀念限制了這個(gè)研究領(lǐng)域的發(fā)展，并且阻礙了針對(duì)壞死相關(guān)疾病的治療手段的開發(fā)，而細(xì)胞壞死是在人類疾病中廣泛存在的。袁鈞瑛教授實(shí)驗(yàn)室揭示了RIPK1 是介導(dǎo)necroptosis 和炎癥的關(guān)鍵蛋白，顛覆了細(xì)胞壞死是不可調(diào)控的傳統(tǒng)學(xué)說。袁鈞瑛教授實(shí)驗(yàn)室發(fā)現(xiàn)的一系列necroptosis 抑制劑（necrostatins）已經(jīng)被廣泛應(yīng)用于證明人類疾病中可調(diào)控細(xì)胞壞死方式的存在，并成為開發(fā)針對(duì)神經(jīng)退行性疾病治療的靶向壞死的新療法的重要候選藥物。參考文獻(xiàn)如下：
a. Degterev A, Hitomi J, Germscheid M, Ch'en IL, Korkina O, Teng X, Abbott D, Cuny GD, Yuan C, Wagner G, Hedrick SM, Gerber SA, Lugovskoy A, Yuan J. Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat Chem Biol. 2008 May;4(5):313-21. PMID: 18408713.
http://www.ncbi.nlm.nih.gov/pubmed/?term=18408713
b. Hitomi J, Christofferson DE, Ng A, Yao J, Degterev A, Xavier RJ, Yuan J. Identification of a molecular signaling network that regulates a cellular necrotic cell death pathway. Cell. 2008 Dec 26;135(7): 1311-23. PMID: 19109899.
http://www.ncbi.nlm.nih.gov/pubmed/?term=19109899
c. Ito Y, Ofengeim D, Najafov A, Das S, Saberi S, Li Y, Hitomi J, Zhu H, Chen H, Mayo L, Geng J, Amin P, DeWitt JP, Mookhtiar AK, Florez M, Ouchida AT, Fan JB, Pasparakis M, Kelliher MA, Ravits J, Yuan J. RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS. Science. 2016 Aug 5;353(6299):603-8. PMID: 27493188.
https://www.ncbi.nlm.nih.gov/pubmed/?term=27493188
d. Ofengeim D, Mazzitelli S, Ito Y, DeWitt JP, Mifflin L, Zou C, Das S, Adiconis X, Chen H, Zhu H, Kelliher MA, Levin JZ, Yuan J. RIPK1 mediates a disease-associated microglial response in Alzheimer's disease. Proc Natl Acad Sci U S A. 2017 Oct 10;114(41):E8788-E8797. PMID: 28904096.
https://pubmed.ncbi.nlm.nih.gov/28904096/
e. Xu D, Jin T, Zhu H, Chen H, Ofengeim D, Zou C, Mifflin L, Pan L, Amin P, Li W, Shan B, Naito MG, Meng H, Li Y, Pan H, Aron L, Adiconis X, Levin JZ, Yankner BA, Yuan J. TBK1 Suppresses RIPK1-Driven Apoptosis and Inflammation during Development and in Aging. Cell. 2018 Sep 6;174(6):1477-1491. PMID: 30146158.
https://pubmed.ncbi.nlm.nih.gov/30146158/
6）袁鈞瑛教授的近期工作首先提出了如何同時(shí)解決細(xì)胞死亡與細(xì)胞穩(wěn)態(tài)打破的新概念，闡明了分子架構(gòu)蛋白TRADD調(diào)控細(xì)胞自噬的新功能，并發(fā)現(xiàn)了Apt-1類可以同時(shí)調(diào)控細(xì)胞死亡和穩(wěn)態(tài)的小分子，為治療神經(jīng)退行性疾病開發(fā)了新方向。參考文獻(xiàn)入下：
Xu D, Zhao H, Jin M, Zhu H, Shan B, Geng J, Dziedzic SA, Amin P, Mifflin L, Naito MG, Najafov A, Xing J, Yan L, Liu J, Qin Y, Hu X, Wang H, Zhang M, Manuel VJ, Tan L, He Z, Sun ZJ, Lee VMY, Wagner G, Yuan J. ModulatingTRADDto restore cellular homeostasis and inhibit apoptosis. Nature. 2020 Sep 23. doi: 10.1038/s41586-020-2757-z. PMID: 32968279
https://pubmed.ncbi.nlm.nih.gov/32968279/ |
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