多學(xué)科合作、融合在化學(xué)生物學(xué)發(fā)展中的重要作用

1、時間時間會議名稱會議名稱2002年年全國化學(xué)生物學(xué)發(fā)展戰(zhàn)略研討會全國化學(xué)生物學(xué)發(fā)展戰(zhàn)略研討會2003年年化學(xué)生物學(xué)研究領(lǐng)域討論會化學(xué)生物學(xué)研究領(lǐng)域討論會2004年年香山會議：香山會議：“化學(xué)生物學(xué)驅(qū)動的功能基因組和創(chuàng)性藥物研究化學(xué)生物學(xué)驅(qū)動的功能基因組和創(chuàng)性藥物研究”2005年年第第40屆屆IUPAC大會的化學(xué)生物學(xué)分會大會的化學(xué)生物學(xué)分會2005年年雙清論壇雙清論壇:“醫(yī)學(xué)基因組和創(chuàng)新藥物研究導(dǎo)向的化學(xué)生物學(xué)醫(yī)學(xué)基因組和創(chuàng)新藥物研究導(dǎo)向的化學(xué)生物學(xué)”2006年年化學(xué)生物學(xué)綜合交叉研究領(lǐng)域化學(xué)生物學(xué)綜合交叉研究領(lǐng)域”小型討論會小型討論會 2004年、年、2006年年中德青年科學(xué)家化學(xué)生物學(xué)研討

2、會中德青年科學(xué)家化學(xué)生物學(xué)研討會2007年年中中-美化學(xué)生物學(xué)專題討論會美化學(xué)生物學(xué)專題討論會自自2001年起年起每兩年一次每兩年一次全國化學(xué)生物學(xué)學(xué)術(shù)會議全國化學(xué)生物學(xué)學(xué)術(shù)會議（至今已舉辦過七屆，第八屆將于（至今已舉辦過七屆，第八屆將于2013年年9月在上海舉行。月在上海舉行。每一屆的參會代表人數(shù)均有大幅增長）。每一屆的參會代表人數(shù)均有大幅增長）。自自2005年起年起每年一次每年一次中美華人化學(xué)教授會議中美華人化學(xué)教授會議（設(shè)有機化學(xué)和化學(xué)生物學(xué)兩個主題，至今已舉辦過九屆，）（設(shè)有機化學(xué)和化學(xué)生物學(xué)兩個主題，至今已舉辦過九屆，）Focused Areas in NIH Directors N

3、ew Innovator Program1Behavioral and Social Science2Chemical Biology3Clinical and Translational Research 4Immunology 5Instrumentation and Engineering6Molecular and Cellular Biology7Neuroscience8High Throughput and Integrative Biology9Quantitative and Computational Biology2004美國美國NIH Directors New Inn

4、ovator Program重點資助的方向重點資助的方向 英國政府對化學(xué)生物學(xué)的資助主要集中在資助包括化學(xué)領(lǐng)域英國政府對化學(xué)生物學(xué)的資助主要集中在資助包括化學(xué)領(lǐng)域EPSRC(Engineering and Physical Sciences Research Council).中國自然科學(xué)基金委在與人類健康相關(guān)領(lǐng)域的經(jīng)費投入情況中國自然科學(xué)基金委在與人類健康相關(guān)領(lǐng)域的經(jīng)費投入情況 (2004-2008； 摘自摘自Nature Chemical Biology, 2006, 4, 515-518)國家自然科學(xué)基金委重大研究計劃國家自然科學(xué)基金委重大研究計劃“基于化學(xué)小分子探針的信號轉(zhuǎn)導(dǎo)過程研究基

5、于化學(xué)小分子探針的信號轉(zhuǎn)導(dǎo)過程研究”（2007-2015）2007-2011， 申請書共計申請書共計607份份 (培育項目培育項目540份，重點項目份，重點項目67份份)。正式資助項目正式資助項目124項，其中培育項目項，其中培育項目110項，重點項目項，重點項目14項項 。已資助總經(jīng)費為已資助總經(jīng)費為9750萬，占總預(yù)算萬，占總預(yù)算65%。2012年重大研究計劃共進行了首批年重大研究計劃共進行了首批6個集成方向和團隊的資助，個集成方向和團隊的資助，2013年公布了第二批年公布了第二批3個項目個項目，總經(jīng)費為總經(jīng)費為5000萬萬，占總預(yù)算占總預(yù)算65%“基于化學(xué)小分子探針的信號轉(zhuǎn)導(dǎo)過程研究基于

6、化學(xué)小分子探針的信號轉(zhuǎn)導(dǎo)過程研究” (2007-2014)正式資助項目正式資助項目124項項:培育項目培育項目110項項重點支持項目重點支持項目14項）項）集成項目集成項目:第一批第一批 6 項項第二批第二批 3 項項Chemical biology in China Generation of chemical probes for studying signal transduction Development of new techniques and methods for detecting the information of signaling processes Biomark

7、er, target and lead discovery based on signal transduction processes Signaling mechanisms of cellular functions based on chemical small molecules下一步我國化學(xué)生物學(xué)要做什么？下一步我國化學(xué)生物學(xué)要做什么？Hot points in Chemical Biology Bioorthogonal Reactions Tracking single molecules at work in living cells Modification of Enha

8、ncer Chromatin Posttranscriptional RNA Modifications Small Molecules for Cell Reprogramming The Challenge and Promise of Glycomics Synthetic biology SYSTEMS BIOLOGY Measurement and modeling approaches bring a big-picture view of biology MAKING CONNECTIONS This network graph shows causal connections

9、among 30,512 genes, 31,459 proteins, and 5,824 small molecules in Genstructs model, which contains 136,362 causal connections that can be evaluated to explain the molecular state changes observed in large-scale systems biology experiments. The red connections represent inhibitions; green, activation

10、; light blue, reaction; dark blue, a product; yellow, catalysis; orange, binding; and black, gene product relations.Bioorthogonal Reactions for Labeling Biomolecules* The reactants in a bioorthogonal reaction should be kinetically, thermodynamically, and metabolically stable before the reaction take

11、s place and not toxic to living systems.* The reaction should yield stable covalent linkages with no or innocuous by products, rapid reactions with high second-order rate constants.* The two bioorthogonal moieties have to react selectively with each other under physiological conditions (ambient temp

12、erature and pressure, neutral pH, aqueous conditions), without either of them cross-reacting with the plethora of chemical functionalities found in living cells.ACS Chem. Biol. 2014, 9, 1620Tracking single molecules at work in living cellsMethods for imaging and tracking single molecules conjugated

13、with fluorescent probes, called single-molecule tracking (SMT), are now providing researchers with the unprecedented ability to directly observe molecular behaviors and interactions in living cells.nature chemical biology | VOL 10, 524 | JULY 2014 |Epigenetic Studies DNA Methylation and Demethylatio

14、n Hestone Acetylation and Deacetylation Noncoding RNA EnhancerEnhancer DNA, commonly 200500 bp in length, contains clustered recognition sites for multiple TFs, representing distinct classes of DNA bindersEnhancers play a central role in driving cell-type-specific gene expression and are capable of

15、activating transcription of their target genes at great distancesRecent large-scale epigenomic mapping revealed unexpected complexity and dynamics of enhancer utilization patterns, with 400,000 putative human enhancers annotated by the ENCODE project alone.Epigenetic Features of Active,Primed, and P

16、oised Enhancers(A) Schematic representation of the major chromatinfeatures found at active enhancers. Enhancers are associated with incorporation of hypermobile nucleosomes containing H3.3/H2A.Z histone variants, which compete for DNA binding with TFs. TFs in turn recruit coactivator proteins that c

17、an modify and remodel nucleosomes. H3K4me1 and H3K27ac are the predominant histone modifications deposited at nucleosomes flanking enhancer elements.(B) Prior to activation, enhancers can exist ina primed state, characterized by the presence ofH3K4me1. Other features that have been associatedwith en

18、hancer priming are presence of pioneerTFs, hypermobile H3.3/H2A.Z nucleosomes, DNA5mC hypomethylation, and hydroxylation (5hmC).(C) Schematic representation of the chromatinlandscape surrounding poised enhancers found inhuman and mouse ESCs. A subset of primedenhancers in ESCs is also marked by H3K2

19、7me3and associated with PRC2. These enhancers arebound by TFs and coactivators and communicatewith their target promotersMolecular Cell 49, 825，March 7, 2013Writers, Readers, and Erasers of,Major Enhancers MarksProteins capable of adding (writers), removing (erasers), and recognizing (readers) major

20、enhancer-associated chromatin modifications, including H3K4me1, H3K9ac, H3K27ac, and5hmC, are shown.DNA Methylation at Enhancers: Driver or Passenger?(1) DNA methylation plays an active role in shaping enhancer landscapes via eviction of TFs from theircognate sites (2) TFs are drivers of hypomethyla

21、ted states, whereas DNA methylation passively fills in sites vacated by TFs departed from decommissioned enhancers. （3）A couple of recent reports argue in favor of the second scenario5-Hydroxymethylcytosine 5hmC has been detected in genomes of several cell types, including ESCs, where it positively

22、correlates with gene activity and is found at promoters, gene bodies, and enhancers With respect to the latter elements and in contrast to 5mC, 5hmC coincides with H3K4me1 and H3K27ac and follows active enhancer marks during differentiation A recent report provided the first single-base-resolution 5

23、hmC map in mouse and human ESCs,revealing that 5hmC is most abundant at both poised and active enhancers, rather than at CpG-rich promoters, as previously suggestedHypermodifications at Positions 34 and 37 in the Anticodon LoopPositions 34 and 37 of the anticodon loop undergo by far the largest dive

24、rsity of posttranscriptional modifications. Highlighted are modified uridines (upper left panel) and guanosines (lower left panel), ubiquitous hypermodifications ensuring correct decoding at the wobble position. Sophisticated purine modifications found at position 37 (upper and lower right panels) p

25、lay roles in reading frame maintenance(A) Adenosine modifications resulting from conjugation to ubiquitous electrophilic metabolites.(B) Chemically sophisticated hypermodifications discovered throughout the past five decades. The year of publication is given in parentheses.(C) The C5-modified cytidi

26、nes related to so-called epigenetic DNA modifications recently discovered. ac6A, 6-acetyladenosine; Arp, 20-O-ribosyladenosine phosphate; oQ, epoxyqueuosine; tm5U, 5-taurinomethyluridine; nm5ges2U, 5-aminomethyl-2-geranyluridine; ho5C, 5-hydroxycytidine; f5C, 5-formyluridineProbing and Perturbing St

27、em Cells with Chemical Biology Murine somatic cells can be“reprogrammed” into induced pluripotent stem cells (iPSCs) with a specific set of transcription factors (TFs), namely, Oct4, Sox2, Klf4, and c-Myc (OSKM) The search of small molecules to improve and/or enable cell reprogramming toward pluripo

28、tency has been most fruitful. During reprogramming, somatic cells must undergo significant epigenetic changes (i.e., histone modifications and DNA methylation) to adopt the ESC-like patterns, small molecules modulating activities of enzymes involved in epigenetic modifications can, therefore, exert

29、profound effects on cell reprogramming. Small Molecules Replacing TFs in the Reprogramming of Somatic Cellssmall molecules combination starting cells TFs required VPA MEFs OSK BIX, BayK or RG108 MEFs OK Kenpaullone MEFs OSM E-616542 MEFs OKM A83-01, AMI-5 MEFs O VPA, CHIR, E-616542, Parnate MEFs O V

30、PA, CHIR, E-616542, Parnate, Forskolin, DZNep MEFs none VPA primary human fibroblast OS CHIR, Parnate human keratinocytes OK NaB, A83-01, PS48, PD neonatal human epidermal keratinocytes O Using cocktails of functionally diverse small molecules to synergistically improve cell reprogramming has been h

31、ighly fruitful. ACS Chem. Biol. 2014, 9, 3444Small Molecules for Cell Reprogramming and Heart Repair: Progress and PerspectiveMin Xie, Nan Cao, and Sheng Ding*ACS Chem. Biol. 2014, 9, 3444The Challenge and Promise of GlycomicsGlycomics is a broad and emerging scientific discipline focused on definin

32、g the structures and functional roles of glycans in biological systems. The staggering complexity of the glycome, minimally defined as the repertoire of glycans expressed in a cell or organism, has resulted in many challenges that must be overcome; these are being addressed by new advances in mass s

33、pectrometry as well as by the expansion of genetic and cell biology studies. Conversely, identifying the specific glycan recognition determinants of glycan-binding proteins by employing the new technology of glycan microarrays is providing insights into how glycans function in recognition and signal

34、ing within an organism and with microbes and pathogens.The promises of a more complete knowledge of glycomes are immense in that glycan modifications of intracellular and extracellular proteins have critical functions in almost all biological pathways.mutations of genes involved in specific glycosylation pathways of anabolism or catabolism might have little effect on cultured cells, but they a