CN102789550A - Meta-analysis method utilizing cross-species similarity - Google Patents
Meta-analysis method utilizing cross-species similarity Download PDFInfo
- Publication number
- CN102789550A CN102789550A CN201110126461XA CN201110126461A CN102789550A CN 102789550 A CN102789550 A CN 102789550A CN 201110126461X A CN201110126461X A CN 201110126461XA CN 201110126461 A CN201110126461 A CN 201110126461A CN 102789550 A CN102789550 A CN 102789550A
- Authority
- CN
- China
- Prior art keywords
- gene
- disease
- group
- module
- expression
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
Landscapes
- Investigating Or Analysing Biological Materials (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Abstract
The invention relates to a meta-analysis method utilizing cross-species similarity. The method based on similarity comparison of cross-species gene modules is disclosed for the first time; through the method, function, action mechanism and the like of a medicine to be tested can be deduced by comparing transcriptome microarray data of the medicine to be tested under a stimulation effect. The method has a great application value in the action mechanism and a disease mechanism research of the medicine.
Description
Technical field
The invention belongs to field of bioinformatics; More specifically, the present invention relates to the element method that species similarity is striden in a kind of utilization.
Background technology
Animal model has irreplaceable effect in drug research.Utilize traditional experimental technique in animal model, to screen the manpower that thousands of kinds of medicines need labor, material resources and time.Bioinformatics, the research that develops into medicine of calculation biology provides a brand-new thinking, and compares with traditional method on the time at cost, has very big advantage.
Animal model very important reason in disease research and medicament research and development is that human disease's sample is unobtainable many comparatively speaking; Particularly when the time series that need set up a disease sample is analyzed; It is more rare that people's disease sample just seems, and this difficulty can well solve in animal model.But activity or the toxicity of utilizing traditional research means to want thousands of kinds of medicines of check on animal model need a large amount of work.
The research that develops into medicine of calculation biology provides a brand-new thinking, can low-cost high-throughout medicine be screened.The representational work in this field is exactly Lamb (Lamb J; Et al. (2006) The Connectivity Map:using gene-expression signatures to connect small molecules; Genes; And disease. (Translated from eng) Science 313 (5795): 1929-1935) wait the people to collect the human gene expression of cells spectrum of the cultivation of handling with the micromolecule of 146 biologically actives; These micromolecule comprise cancer therapy drug, estrogen, microbiotic etc.The author draws that the thought of similarity comparison attempts to set up between medicine, " contact figure (connectivity map) " between disease, between medicine and disease.Many researchers also utilize " contact figure " to seek side effects of pharmaceutical drugs, drug target etc.For example, those skilled in the art through glucocorticoid relatively responsive with non-sensitive leukemic lymphoblastoid cellular expression spectrum chip data, successfully predict and proved that Rapamycin can induce the susceptibility of lymph for glucocorticoid.Also found new HSP90 suppressant through same method, because this suppressant and existing suppressant celastrol and gedunin have good similarity, result of experiment has also proved this point.Those skilled in the art also utilize 250 gene expression profile data obtaining from PredTox (http://www.innomed-predtox.com) database as a reference; As inquiry, found that at reference database 5 kinds have the compound of similar toxicity with it with compound griseofulvin.
Although " contact figure " obtained very big success, it also has significant limitation.Wherein be exactly " contact figure " data centralization and only contain people's gene expression profile data, and chip data that can only the end user comes to compare with it.For the chip of expression spectrum that can use other species carries out similarity relatively, must use infraspecific data set, this point is unpractical.The large-scale application that has limited " contact figure " more in addition is the algorithm aspect that it adopts, and " contact figure " at first need pick out the gene that can represent cell state of living in.The instability of these representational genes can cause result's instability.
Animal model all has application in the research of multiple human relevant disease, particularly ought relate to the situation that the human sample of moral reason is difficult to acquisition.In addition, the cost of animal model also is much smaller.In fields such as Alzheimer's disease, cancer, new drug developments, animal model has all obtained good application.Research has confirmed that animal model can predict 71% the toxicity of medicine in human body.On the other hand; Cell in each tissue of morbid state servant _ ENREF_5 is difficult to obtain; Therefore often use cell model and substitute, but external (cellular level) and the interior real physiological conditions of body and inconsistent, and this contradiction does not then exist with animal model the time.
Therefore, how animal model and data with existing data are effectively integrated, be applied to analyze medicine apace, well and the validity of human body diseases is one needs research and perfect problem badly.
Summary of the invention
The object of the present invention is to provide a kind of utilization to stride the element method of species similarity.
In first aspect of the present invention, a kind of method that species are analyzed the latent effect of medicine to be measured of striding is provided, comprising:
(1) gene expression profile of acquisition testing group and control group; This testing group is the animal disease model after the drug-treated to be measured; This control group is not with the animal disease model of drug-treated to be measured;
(2) with the conversion of the dna homolog in the gene expression profile of the animal disease model of (1) adult's homologous gene, thereby the gene in the gene expression profile of animal disease model is converted into people's homologous gene, obtains corresponding people's homologous gene and expression;
(3) testing group and the homogenic expression of control group people are compared, remove in the testing group the not remarkable part of (difference is not remarkable on the statistics) of differential expression; People's homologous gene to differential expression in the testing group remarkable (significant difference on the statistics) carries out the enrichment analysis (cluster analysis) of gene ontology module, obtains the gene ontology module of significant difference;
(4) express spectra before and after various known drugs are handled of this kind of collection disease association from reference database is handled the express spectra of front and back to each known drug, and the significant gene of collection and treatment front and back differential expression carries out the enrichment analysis of gene ontology module; Thereby,, obtain the gene ontology module of one group of significant difference to each known drug;
(5) (3) the gene ontology module that obtains and each group gene ontology module that (4) obtain carried out similarity relatively; Quantity according to similarity gene module is carried out rank to corresponding known drug (like micromolecular compound) in the reference database; Similarity gene module number is relevant more more at most; Confirm maximally related several medicines, they are and the immediate known drug of pharmic function to be measured, thereby learn the latent effect of medicine to be measured.
In another aspect of this invention, provide a kind of analysis to disease animal model effectively or the method for the potential drug of pathogenic (or spinoff) is arranged, this method comprises:
(1) gene expression profile of acquisition testing group and control group; This testing group is the animal model under the morbid state; This control group is the animal model under the health status;
(2) with the conversion of the dna homolog in the gene expression profile of the animal disease model of (1) adult's homologous gene, thereby the gene in the gene expression profile of animal model is converted into people's homologous gene, obtains corresponding people's homologous gene and expression;
(3) testing group and the homogenic expression of control group people are compared, remove in the testing group the not remarkable part of (difference is not remarkable on the statistics) of differential expression; People's homologous gene to differential expression in the testing group remarkable (significant difference on the statistics) carries out the enrichment analysis (cluster analysis) of gene ontology module, obtains the gene ontology module of significant difference;
(4) express spectra before and after various known drugs are handled of this kind of collection disease association from reference database is handled the express spectra of front and back to each known drug, and the significant gene of collection and treatment front and back differential expression carries out the enrichment analysis of gene ontology module; Thereby,, obtain the gene ontology module of one group of significant difference to each known drug;
(5) (3) the gene ontology module that obtains and each group gene ontology module that (4) obtain carried out similarity relatively; Quantity according to similarity gene module is carried out rank to corresponding known drug (like micromolecular compound) in the reference database, and similarity gene module number is relevant more more at most;
(6) confirm maximally related several medicines, they are the potential drugs that disease animal model had pathogenic (or spinoff); Confirm several least relevant medicines, they are to the effective potential drug of this disease.
In another preference, in (4), described reference database is mainly derived from Connectivity Map (cMap), and it has been put down in writing between various medicine-diseases and has got in touch, and the express spectra before and after the drug-treated.
In another preference, described medicine to be measured is compound (like a micromolecular compound).
In another preference, in (2), carry out the homology conversion through Roundup homologous gene database.
In another preference, 3) in, the threshold value of differential expression is set, show that difference is not remarkable, shows significant difference and be higher than this threshold value if be lower than this threshold value.
In another preference, the threshold value of this differential expression is that 2 times of differences (that is: the P value is less than 0.01) are expressed.
In another preference, in (3), the method for utilizing hypergeometry check is carried out the enrichment analysis of gene ontology module to people's homologous gene of the significant difference picked out.
In another preference, in (5), adopt the similarity of Kolmogorov-smirnov algorithm computation gene ontology module.
In another preference, described animal is selected from (but being not limited to): mouse, rabbit, monkey, ox, sheep.
In another preference, said method also is used for:
The same or analogous medicine of enrichment function; Or
Well whether the assessment animal disease model anthropomorphic dummy's disease.
Others of the present invention are because the disclosure of this paper is conspicuous to those skilled in the art.
Description of drawings
Fig. 1, OGMES2 process flow diagram.
The treatment scheme synoptic diagram of the express spectra of Fig. 2, control group and test group.
Embodiment
The inventor is through extensive studies; Develop a kind of first based on striding species gene module similarity method relatively; Through this method, only need to transcribe the function that core assembly sheet data just can be inferred this medicine to be measured, mechanism of action etc. under the medicine irritation effect more to be measured.This method has huge using value at mechanism of drug action in the pathogenic mechanism research.
In order to solve the limitation of " contact figure " (connectivity map); And make full use of the data of animal disease model; They are utilized at medicine again; Better effect of performance in pharmic function research and the disease research, the inventor has developed a kind of new method, comprising: (1) obtains the gene expression profile of testing group and control group; This testing group is the animal disease model after the drug-treated to be measured; This control group is not with the animal disease model of drug-treated to be measured; (2) with the conversion of the dna homolog in the gene expression profile of the animal disease model of (1) adult's homologous gene, thereby the gene in the gene expression profile of animal model is converted into people's homologous gene, obtains corresponding people's homologous gene and expression; (3) testing group and the homogenic expression of control group people are compared, remove in the testing group the not remarkable part of (difference is not remarkable on the statistics) of differential expression; People's homologous gene to differential expression in the testing group remarkable (significant difference on the statistics) carries out the enrichment analysis (cluster analysis) of gene ontology module, obtains the gene ontology module of significant difference; (4) express spectra before and after various known drugs are handled of this kind of collection disease association from reference database is handled the express spectra of front and back to each known drug, and the significant gene of collection and treatment front and back differential expression carries out the enrichment analysis of gene ontology module; Thereby,, obtain the gene ontology module of one group of significant difference to each known drug; (5) (3) the gene ontology module that obtains and each group gene ontology module that (4) obtain carried out similarity relatively; Quantity according to similarity gene module is carried out rank to corresponding known drug (like micromolecular compound) in the reference database; Similarity gene module number is relevant more more at most; Confirm maximally related several medicines, they are and the immediate known drug of pharmic function to be measured, thereby learn the latent effect of medicine to be measured.
In addition, method of the present invention also can be used for being directed against the potential drug that disease animal model screens medicine or causes spinoff.As long as plant in above-mentioned (1) step, obtain the gene expression profile of testing group and control group; This testing group is the animal model under the morbid state; This control group is the animal model under the health status; And last in above-mentioned (5) step confirmed maximally related several medicines, and they are the potential drugs that disease animal model had pathogenic (or spinoff); Confirm several least relevant medicines, they are to the effective potential drug of this disease.
Preferably; In described test group and the control animals model; Except drug-treated to be measured be untreated on distinct, others such as animal feeding mode, animal age etc. all are identical, objective, the correctness of the comparative result that helps like this obtaining.
Gene expression profile (Gene Expression Profile) is meant the non-bias cDNA library that is in the cell or tissue under a certain particular state through structure; The large-scale cDNA order-checking; Collect cDNA sequence fragment, qualitative, its mRNA colony composition of quantitative test; Thereby describe this specific cells or be organized in gene expression kind and the gt under the particular state, the tables of data that is compiled into so just is called gene expression profile.Between the preparation of gene expression profile and the gene expression profile data relatively is technology well known to those skilled in the art; In the prior art instrument of test cdna express spectra has been arranged also at present, and the instrument, program or the software that are used for comparison between the gene expression profile.
The gene of animal model and people's gene database are compared, thereby find its homologous gene, this is the technology that those skilled in the art know.Those skilled in the art are very clear, in the essential information of gene expression profile, comprised gene I information, with and abundance (expression) information.Therefore; " gene expression profile of animal model and people's related gene expression spectrum reference data set are compared " described in the present invention; Come down to gene I information based on animal model; Find the corresponding homogenic id information of philtrum, thereby abundance (expression) information in the gene expression profile that records in this people's gene I information and the animal model is set up related (promptly " obtaining corresponding people's homologous gene and expression ").
Under drug-treated or situation about not handling, inapparent those genes of differential expression, normally independent basis because of, medicine does not change its expression way.Therefore, the testing group data need compare with the control group data, thereby remove inapparent those gene informations of differential expression.
The cluster analysis of gene ontology module and gene ontology module is a technology well known in the art, and ripe statistical analysis technique has been arranged, like the method for hypergeometry check.
The similarity analysis of gene ontology module also is a technology well known in the art, and ripe statistical analysis technique has been arranged, as adopting Kolmogorov-smirnov algorithm or method similar with it.
Described reference database be mainly derived from " contact figure " (Connectivity Map, cMap).This is the database that those skilled in the art have formerly set up.Chip of expression spectrum data have wherein been collected more than 1300 kinds of micromolecular compounds.
A principal feature of method of the present invention is available data in " contact figure " are extended to except that the people in other the species and goes, and in addition, this method can also be used to assessing the truth whether animal model can be good at anthropomorphic dummy's disease.In order to realize the comparison between different plant species; Method of the present invention is utilized Roundup, and (Deluca TF, et al. (2006) Roundup:a multi-genome repository of orthologs and evolutionary distances. (Translated from eng) Bioinformatics 22 (16): 2044-2046) the homologous gene information in the data is with the gene conversion adult's of other species gene.
Although " contact figure " of the prior art proved its validity in many aspects, also the research confirmation its in the validity of the express spectra similarity of striding species in relatively.And the present invention improves in this respect, has set up a platform of striding the species similarity comparative analysis based on " contact figure "; And the feasibility of the proof inventor's platform.
Through testing some known express spectra data, proved that method of the present invention can be utilized to stride species, cross-platform express spectra data and carry out similarity relatively, and aspect prediction medicine unknown function and the clinical practice that some are possible certain value has been arranged.
Can set up network inquiry, the analytic system of friendly interface based on method provided by the invention, thereby be convenient for people to use and analyze.
Major advantage of the present invention is:
(1) the present invention is applied to the present method based on the similarity comparison in the different animal model, and has proved the feasibility of method in the comparison of striding the species platform of similarity comparison, and this method has huge using value in pathogenic mechanism research.
(2) before research all is based on the comparison between the same species, stride between species relatively still for the first time. therefore method of the present invention has overcome people's technological prejudice.
(3),, and aspect mechanism of drug action, given explaination successfully for diseases such as Alzheimer's disease, anoxic find suitable curative drug through platform of the present invention.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in the restriction scope of the present invention.The experimental technique of unreceipted actual conditions in the following example, usually according to normal condition, or the condition of advising according to manufacturer.
The inventor has developed based on homologous gene module ratio of similitude method and has set up getting in touch between micromolecular compound and animal disease model.
With mouse Cancerous disease model is example; After giving micromolecular compound to be measured; Obtain the gene expression profile data (data are made up of gene I and expression values) of test group and control group mice respectively, the gene I of mouse is changed adult's gene I (homologous gene conversion); Then test group and the homogenic expression of control group people are compared, remove differential expression inapparent part on statistics in the testing group; Keep differential expression significant people's homologous gene on statistics in the testing group; Gene information enrichments after then these being changed are on corresponding gene ontology module.The correlativity of relatively coming micromolecular compound more to be measured and Animal diseases through the gene ontology intermodule.Concrete flow process such as Fig. 1.The inventor is called OGEMS2 with this method.
Test group (testing group): give the mouse model that micromolecular compound to be measured stimulates;
Control group: not giving micromolecular compound to be measured stimulates, and others such as nursing are with the mouse model of test group.
Perhaps,
Test group: mouse disease model;
Control group: normal (non-disease) mouse.
Data Source
The inventor obtains the chip of expression spectrum data set that known small molecules stimulates servant's cancer relevant cell, database as a reference from contact figure (connectivity map); Download address: http://www.broda.mit.edu/cmap/ obtains the chip gene expression profile data about known small molecules stimulation servant's cancer relevant cell; Database as a reference after treatment.Treatment scheme is: the express spectra before and after handling to each known small molecules, and the significant gene of differential expression carries out the enrichment analysis of gene ontology module before and after the collection and treatment; To each known drug, obtain the gene (according to the changes in gene expression multiple value, gene is carried out rank, obtain the rank of changes in gene expression value) of one group of significant difference like Fig. 2.
The homologous gene conversion
The gene I of given mouse is through the gene of Roundup database (http://round.hms.harvard.edu/site/index.php) with homologous information conversion adult.Roundup is a homogenic database.According to RSD (Reciprocal Smallest Distance) (Wall DP, Fraser HB, & Hirsh AE (2003); Detecting putative orthologs. (Translated from eng) Bioinformatics 19 (13): 1710-1711) algorithm calculates the distance of homology.
GEMS2
After the homology conversion process,, pick out the gene (fold that the acquiescence employing is 2 times is as the threshold value of differential expression) of differential expression through the gene expression profile data (test group) of comparison stimulus function cells and the express spectra data (control group) under the non-stimulation.Utilize the method for hypergeometry check that these genes are carried out gene ontology (Gene ontology) enrichment analysis then, choose and compare the p value with control group less than 0.01 gene ontology module (GO module; GOM).Based on the GO module of choosing, calculate the similar situation of each gene ontology module in the express spectra that relevant disease obtains in data query and the reference database after small-molecule drug stimulates.Adopt the kolmogorov-smirnov algorithm to calculate similarity (Lamb J; Et al. (2006) The Connectivity Map:using gene-expression signatures to connect small molecules; Genes, and disease. (Translated from eng) Science 313 (5795): 1929-1935).Be that with places different in the article Lamb etc. relatively are applied in similarity on the whole express spectra data, the present invention then concentrates on each gene module.The result of output is the matrix of a similarity, and every row are being represented each medicine in the reference database, and every row is representation feature gene module then.Numerical value in the matrix data frame has then been represented the size of compound and data query each gene module similarity in the reference database.
To comprise maximally related (comprising that positive correlation and parafacies close) 10 known small molecules medicines among the result, and in the result, list their maximally related gene ontology modules (GO module), this module is that positive correlation or parafacies close, and all will in the result, show.
Interpretation of result
Quantity according to similarity gene module is carried out rank to the micromolecular compound in the reference database, generally chooses the compound of rank preceding 10 and further analyzes.
When test group is to give the mouse model that micromolecular compound to be measured stimulates; When control group stimulates for not giving micromolecular compound to be measured; Confirm maximally related 10 known compounds, they are and the immediate known drug of pharmic function to be measured, thereby learn the latent effect of medicine to be measured.
When test group is a mouse disease model, when control group is normal (non-disease) mouse, confirm maximally related 10 known compounds, they are the potential drugs that disease animal model had pathogenic (or spinoff); Confirm least 10 known compounds of relevant (parafacies pass), they are to the effective potential drug of this disease.
The compound that embodiment 2, searching have identity function
At first, the inventor has verified that the described species analytical approach of striding can seek out the micromolecule with identity function.
From GEO (GDS:3002, http://www.ncbi.nlm.nih.gov/gds? Term=gds3002) go up download and obtained 7 TSA (a kind of histon deacetylase (HDAC) inhibitors; Trichostatin A) the gene expression profile data of the mouse bone-forming cell (MC3T3-E1) under the spread effect, 7 data comprise 3 repeating data and 4 control groups under the TSA stimulation, concrete data are following:
Test group
GSM234802(http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc＝GSM234802)：TSA?Treated?Rep?1；
GSM234803(http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc＝GSM234803)：TSA?Treated?Rep?2；
GSM234804(http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc＝GSM234804)：TSA?Treated?Rep?3。
Control group
GSM234794(http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc＝GSM234794)：DMSO?Treated?Control?1；
GSM234795(http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc＝GSM234795)：DMSO?Treated?Control?2；
GSM234796(http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc＝GSM234796)：DMSO?Treated?Control?3；
GSM234797(http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc＝GSM234797)：DMSO?Treated?Control?4。
The inventor according to the method described in the embodiment 1, carries out the similarity search with the express spectra data of the above-mentioned acquisition gene expression profile data as animal model, has obtained 10 the highest compounds of score, like table 1.
Wherein ,+represent positively related GO, the GO of-expression negative correlation.
Among the result; TSA has occurred 7 times, and other 3 results are to be respectively Valporic acod, Vorinostat; HC toxin; Although their structure is very inequality, in proved they all be hdac inhibitor (referring to Gottlicher, M.et al.Valproic acid defines a novel class of HDAC inhibitors inducin g differentiation of transformed cells.EMBO J 20; 6969-6978, doi:10.1093/emboj/20.24.6969 (2001); Fedier; A.et al.; The histone deacetylase inhibitors suberoylanilide hydroxamic (Vorinostat) and valproic acid induce irreversible and MDR1-independent resistance in human colon cancer cells.Int J Oncol 31,633-641 (2007); Or Deubzer; H.E.et al.Histone deacetylas inhibitor Helminthosporium carbonum (HC)-toxin suppresses the malignant phenotype of neuroblastoma cells.Int J Cancer 122; 1891-1900, doi:10.1002/ijc.23295 (2008).The nearly all result of table 1 presentation of results is to be positively related with what inquire about, and this is consistent with the result of the inventor through the document inquiry.
This result has proved that method of striding the comparison of species of the present invention can find the micromolecular compound with identity function.
Contact between embodiment 3, exploration micromolecule and the mouse disease model
The method of OMGES2 can be used for searching for the possible treatment means of certain disease equally, and this function can be found existing medicine new purposes clinically.The inventor has tested the data of 3 relevant mouse disease models respectively, is respectively Alzheimer's disease, air hunger and synovial sarcoma.
1, Alzheimer's disease disease model
The inventor seeks the medicine sick relevant with Alzheimer's disease through OGEMS2.Alzheimer's disease is a kind of nerve degenerative diseases that can not cure.The data of using are transgene mouse models; This mouse model has been expressed sudden change (the Nordenberg J of people APP (amyloid precusor protein) on No. 695 amino acid; Et al. (1992) Novobiocin-induced anti-proliferative and differentiating effects in melanoma B16. (Translated from eng) Br J Cancer 65 (2): 183-188), suffer from the Alzheimer disease.This data centralization has comprised 6 chip datas; 2 normal hippocampal cell data are as the control group data; Is 4 that APP transgenic mice data are as test group data (GEO:GSE14499, http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi? Acc=GSE14499) concrete data are following:
Test group:
GSM362128(http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc＝GSM362128)：Hippocampus，APP?transgenic?animals，GFP?treated，biological?rep1；
GSM362131(http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc＝GSM362131)：Hippocampus，APP?transgenic?animals，GFP?treated，biological?rep2；
GSM362134(http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc＝GSM362134)：Hippocampus，APP?transgenic?animals，GFP?treated，biological?rep3；
GSM362136(http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc＝GSM36213?6)：Hippocampus，APP?transgenic?animals，GFP?treated，biological?rep4。
Control group:
GSM362138(http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc＝GSM362138)：Hippocampus，non-transgenic?animals，sham?lesion，biological?rep2；
GSM362130(http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc＝GSM362130)：Hippocampus，non-transgenic?animals，sham?lesion，biological?rep1。
The inventor according to the method described in the embodiment 1, carries out the similarity search with the express spectra data of the above-mentioned acquisition gene expression profile data as animal model, has obtained 10 the highest compounds of score, result such as table 2.
Table 2, with 10 kinds of maximum medicines of mouse Alzheimer's disease model hippocampal cell chip of expression spectrum data similarity GOM
It is to be negative correlation with the Alzheimer's disease disease that 6 kinds of medicines are arranged among 10 results, is indicating that these medicines possibly have certain therapeutic action to Alzheimer's disease.Wherein, Nordihydroguaiaretic acid can destroy beta-amyloyd patch (Nagahara AH, et al. (2009) Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer ' s disease. (Translated from eng) the Nat Med 15 (3): 331-337) of Alzheimer's disease.The multiple pathological characteristics of Tretinoin (Retinoid) and Alzheimer's disease all has relation (Shudo K; Fukasawa H; Nakagomi M, & Yamagata N (2009) Towards retinoid therapy for Alzheimer ' s disease. (Translated from eng) Curr Alzheimer Res 6 (3): 302-311), comprise the starch spot; Inflammation, Apoptosis and neurological etc.And Nordihydroguaiaretic acid that the result shows and Tretinoin are negative correlation with Alzheimer's disease in most gene ontology modules relation, the inventor's result and document have confirmed that all these two kinds of medicines have certain therapeutic action for Alzheimer's disease.Estradiol and Alpha-Estradiol can suppress the sick caused inflammatory reaction (Valles SL, et al. (2010) Estradiol or genistein prevent Alzheimer ' s disease-associated inflammation correlating with an increase PPAR gamma expression in cultured astrocytes. (Translated from eng) Brain Res 1312:138-144) of Alzheimer's disease through the expression of raising PPARgamma.Monorden is also referred to as radicicol, can combine Hsp90 and change its function, and the pathology of the nervus retrogression of HSP90 and Alzheimer's disease is relevant.LY-294002 is through suppressing transhipment and metabolism (the Shineman DW that PI3K suppresses APP; Dain AS; Kim ML, & Lee VM (2009) Constitutively active Akt inhibits trafficking of amyloid precursor protein and amyloid precursor protein metabolites through feedback inhibition of phosphoinositide 3-kinase. (Translated from eng) Biochemistry 48 (17): 3787-3794).
In remaining four kinds of medicines; Prazosin is mainly used in hypertension; Treatment of diseases such as hypertrophy of the prostate; A current research confirms that prazosin can increase the weight of symptom (Wang LY, et al. (2009) Prazosin for the treatment of behavioral symptoms in patients with Alzheimer disease with agitation and aggression. (Translated from eng) the Am J Geriatr Psychiatry 17 (9): 744-751) of Alzheimer's disease.Fulvestrant is a very significant medicine; It can either the antagonism ERs; Can suppress HSP90 equally; And cause that he is at intracellular degraded (Han G, et al. (2009) Essential role of the 90-kilodalton heat shock protein in mediating nongenomic estrogen signaling in coronary artery smooth muscle. (Translated from eng) J Pharmacol Exp Ther 329 (3): 850-855).Consider and show among the result that Fulvestrant becomes positive correlation with Alzheimer's disease; The inventor infers that estrogen pathway maybe be more even more important than HSP90 path in the Alzheimer disease, and the inventor infers that one of these side effects of pharmaceutical drugs possibly be exactly to increase the weight of or induce the Alzheimer disease.
2, anoxia model
Then; The inventor has tested the anoxia model of mouse; Data be Laifenfeld etc. do about mouse (Laifenfeld D under the situation of oxygen concentration from 21% to 6%; Et al. (2010) The role of hypoxia in 2-butoxyethanol-induced hemangiosarcoma. (Translated from eng) Toxicol Sci 113 (1): 254-266), the chip of expression spectrum data when continuing 30 minutes.Wherein mouse has been disposed 120 minutes again in addition in 6% oxygen concentration, gets the marrow of left side humerus.Does the inventor obtain wherein 7 chip datas (GEO:GSE17796, http://www.ncbi.nlm.nih.gov/gds? Term=GSE17796), concrete data are following:
Test group:
GSM444147(http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc＝GSM444147)：bone?marrow-hypoxia-2hours-rep?3；
GSM444145(http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc＝GSM444145)：bone?marrow-hypoxia-2hours-rep?1；
GSM444148(http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc＝GSM444148)：bone?marrow-hypoxia-2hours-rep?4；
GSM444146(http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc＝GSM444146)：bone?marrow-hypoxia-2hours-rep?2。
Control group:
GSM444144(http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc＝GSM444144)：bone?marrow-vehicle-2hours-rep?3；
GSM444142(http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc＝GSM444142)：bone?marrow-vehicle-2hours-rep?1；
GSM444143(http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc＝GSM444143)：bone?marrow-vehicle-2hours-rep?2。
The inventor according to the method described in the embodiment 1, carries out the similarity search with the express spectra data of the above-mentioned acquisition gene expression profile data as animal model, has obtained 10 the highest compounds of score, result such as table 3.
Table 3, with 10 kinds of maximum medicines of anoxia in mice model cell chip of expression spectrum data similarity GOM
Have 9 to be proportionate fully among 10 results, and all compounds are all checked and verify relevant with air hunger through document with data query.Wherein, Resveratrol has occurred 3 times; It can suppress accumulation (the Zhang Q of oxygen deficient induction factor 1-Alpha and VEGF under the anaerobic condition; Et al. (2005) Resveratrol inhibits hypoxia-induced accumulation of hypoxia-inducible factor-1Alpha and VEGF expression in human tongue squamous cell carcinoma and hepatoma cells. (Translated from eng) Mol Cancer Ther 4 (10): 1465-1474), so it mainly under anaerobic conditions has a protection mechanism to body.Deferoxamine; Can with the iron combined with radical; State through the conversion ferric ion is simulated anaerobic condition (Vengellur A; Phillips JM, Hogenesch JB, & LaPres JJ (2005) Gene expression profiling of hypoxia signaling in human hepatocellular carcinoma cells. (Translated from eng) Physiol Genomics 22 (3): 308-318).Ionomycinis generally is used for improving intracellular calcium ion concentration in experiment; Confirm in the research that it can improve the activity of calpain in the rat proximal tubule tissue and simulate anaerobic environment (Edelstein CL, et al. (1996) Modulation of hypoxia-induced calpain activity in rat renal proximal tubules. (Translated from eng) Kidney Int 50 (4): 1150-1157).Sirolimus is a kind of mTOR suppressant; Activity (the Carver DJ that can suppress hypoxia inducible factor; Gaston B; Deronde K, & Palmer LA (2007) Akt-mediated activation of HIF-1 in pulmonary vascular endothelial cells by S-nitrosoglutathione. (Translated from eng) Am J Respir Cell Mol Biol 37 (3): 255-263).TSA then can suppress blood vessel hyperplasia (Yang QC, et al. (2006) Inhibition of hypoxia-induced angiogenesis by trichostatin A via suppression of HIF-1a activity in human osteosarcoma. (Translated from eng) the J Exp Clin Cancer Res 25 (4): 593-599) that anoxic causes through the activity that suppresses HIF-a.Research confirms that Rottlerin can quicken spending rate (Thomas R & Kim MH (2007) Targeting the hypoxia inducible factor pathway with mitochondrial uncouplers. (Translated from eng) the Mol Cell Biochem 296 (1-2): 35-44) of oxygen in the cell.There is report to confirm that troglitazone can alleviate injury (Elchalal U, et al. (2004) Troglitazone attenuates hypoxia-induced injury in cultured term human trophoblasts. (Translated from eng) the Am J Obstet Gynecol 191 (6): 2154-2159) of anoxic to human body.
3, synovial sarcoma model
At last; The inventor has tested mouse synovial sarcoma model; This mouse model has been expressed people SYT-SSX fusion (Haldar M, Hancock JD, Coffin CM; Lessnick SL, & Capecchi MR (2007) A conditional mouse model of synovial sarcoma:insights into a myogenic origin. (Translated from eng) Cancer Cell 11 (4): 375-388).Synovial sarcoma is a kind of very rare cancer, generally occurs in the joint of upper limbs or lower limb.Has the inventor tested the data of 9 chips, 5 tumours, 4 contrasts, (GEO:GDS2698, http://www.ncbi.nlm.nih.gov/gds? Term=gds2698):
Control group:
GSM148507(http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc＝GSM148507)：Wild?Type?Skeletal?Muscle?Sample(Hind?limb)；
GSM148508(http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc＝GSM148508)：Wild?Type?Skeletal?Muscle?Sample(Intercostal)；
GSM148509(http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc＝GSM148509)：Wild?Type?Skeletal?Muscle?Sample(forelimb)；
GSM148510(http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc＝GSM148510)：Wild?Type?Skeletal?Muscle?Sample(Hind?limb?2)。
Test group:
GSM148511(http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc＝GSM148511)：Tumor?from?MYF-5?CRE/SSM2?mouse?CC23；
GSM148512(http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc＝GSM148512)：Tumor?from?MYF-5?CRE/SSM2?mouse?CC17-B；
GSM148513(http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc＝GSM148513)：Tumor?from?MYF-5?CRE/SSM2?mouse?CC17-A；
GSM148514(http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc＝GSM148514)：Tumor?from?MYF-5?CRE/SSM2?mouse?SSM5；
GSM148515(http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc＝GSM148515)：Tumor?from?MYF-5?CRE/SSM2?mouse?SSM4。
The inventor according to the method described in the embodiment 1, carries out the similarity search with the express spectra data of the above-mentioned acquisition gene expression profile data as animal model, has obtained 10 the highest compounds of score, result such as table 4.
Table 4, with 10 kinds of maximum medicines of anoxia in mice model cell chip of expression spectrum data similarity GOM
10 medicines of listing in the indicator gauge as a result all become negativity relevant with synovial sarcoma, show that these medicines possibly be this sick drug candidates of treatment.Pirinixic acid is a kind of blood lipid-lowering medicine; And possibly be the antagonist of PPARa; And research confirms that the PPARa antagonist can suppress growth of tumor (Panigrahy D, et al. (2008) PPARAlpha agonist fenofibrate suppresses tumor growth through direct and indirect angiogenesis inhibition. (Translated from eng) Proc Natl Acad Sci U S A 105 (3): 985-990).15-delta prostaglandin J2 can strengthen antitumor activity (the Fulzele SV of docetaxel; Et al. (2007) 15-Deoxy-Delta 12,14-prostaglandin J2 enhances docetaxel anti-tumor activity against A549 and H460 non-small-cell lung cancer cell lines and xenograft tumors. (Translated from eng) Anticancer Drugs 18 (1): 65-78).Mercaptopurine is medicine (the Rose DP of treatment leukaemia and chronic non_hodgkin lymphoma; Connolly JM; Rayburn J, & Coleman M (1995) Influence of diets containing eicosapentaenoic or docosahexaenoic acid on growth and metastasis of breast cancer cells in nude mice. (Translated from eng) J Natl Cancer Inst 87 (8): 587-592).Docosahexaenoic acid can suppress growth (the Zhang YG of human breast cancer cell; Du Q; Fang WG; Jin ML, & Tian XX (2008) Tyrphostin AG1478 suppresses proliferation and invasion of human breast cancer cells. (Translated from eng) Int J Oncol 33 (3): 595-602).Tyrphostin A and G1478 can suppress the growth and the increment of human breast cancer cell.Novobiocin possibly be the melanomatous drug candidate of treatment.Carbamazepine can suppress human breast cancer cell growth (Meng QW, et al. (2006) [Inhibitory effect of carbamazepine on proliferation of estrogen-dependent breast cancer cells]. (Translated from chi) Ai Zheng 25 (8): 967-973).TSA and valporic acid are histon deacetylase (HDAC) inhibitors, and this point is considered to a good target spot of oncotherapy always.
4, whether the test mouse is the good model of diabetes
Research confirms that mouse is not the good model of people's diabetes, because the AR expression in the mouse body is than low many of people.Express spectra data (GEO, GSE14888, the http://www.ncbi.nlm.nih.gov/gds of the adipocyte of the mouse 3t3-11 under the melbine of selecting for use stimulates? Term=gse14888), concrete data are following:
Test group:
GSM372036(http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc＝GSM372036)：3T3-L1?adipocyte?tissue?culture，metformin?fed，biological?rep1；
GSM372038(http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc＝GSM372038)：3T3-L1?adipocyte?tissue?culture，metformin?fed，biological?rep3；
GSM372037(http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc＝GSM372037)：3T3-L1?adipocyte?tissue?culture，metformin?fed，biological?rep2。
Control group:
GSM372030(http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc＝GSM372030)：3T3-L1?adipocyte?tissue?culture，LA?fed，biological?rep1；
GSM372032(http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc＝GSM372032)：3T3-L1?adipocyte?tissue?culture，LA?fed，biological?rep3；
GSM372031(http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc＝GSM372031)：3T3-L1?adipocyte?tissue?culture，LA?fed，biological?rep2。
The inventor according to the method described in the embodiment 1, carries out similarity search through OGEMS2 with the express spectra data of the above-mentioned acquisition gene expression profile data as animal model, has obtained 10 the highest compounds of score, and the result is presented in the table 5.
Table 5: stimulate 10 kinds of maximum medicines of mouse adipocyte chip of expression spectrum data similarity GOM down with melbine
Have only 15-delat prosaglandin J2 relevant with diabetes among the result, it is the part of PPARgamma acceptor.Other drug does not all have document to confirm and the relation of diabetes, therefore can think that mouse is not a good model of diabetes, and method of the present invention can be used for assessing the quality of animal model.
5, excavate biological mechanism
The inventor has done the analysis, particularly Fulvestrant of the degree of depth, Alpha-Estradiol and Monorden to the example of Alzheimer's disease.Alpha-Estradiol is main estrogen, and Monorden is a kind of HSP90 suppressant, and these two kinds of medicines all become negative correlation with Alzheimer's disease eventually in the result.Fulvestrant is the suppressant that a kind of estrogenic blocking agent is again HSP90, shows with Alzheimer's disease in the result to be proportionate.Discussed in the preceding text, the HSP90 suppressant all becomes to attach relevant with Alzheimer's disease with estrogen.Therefore, the inventor infers that the positive correlation of Fulvestrant explained in the Alzheimer disease that the estrogen path is bigger than the influence of Hsp90 path.
Research proof HSP90 can combine and regulate and control their activity (Fliss AE with the hormone acceptor; Benzeno S; Rao J, & Caplan AJ (2000) Control of estrogen receptor ligand binding by Hsp90. (Translated from eng) J Steroid Biochem Mol Biol 72 (5): 223-230).Therefore, it has been generally acknowledged that Monorden is through acting on the HSP90 acceptor and then reconciling the activity of estrogen pathway.Yet according to the inventor's result, the GO module of Alpha-Estradiol mainly is about lipid metabolism (GO:0008610; GO:0006629 sees table 6), and Monorden mainly is (GO:0016126 on sterol metabolism module; GO:0016125, table 6) and Alzheimer's disease positive correlation.These two diverse biology proof HSP90 possibly not be relevant with Alzheimer's disease through estrogen pathway, should pass through an other path.
The difference of icp gene body module can find out, Fulvestrant has been Duoed two modules than Alpha-Estradiol and monoden: phosphoglyceride metabolic process (GO:0006650) and phosphatide biosynthetic process (GO:0008654).Therefore, the inventor can infer from the result, and to alleviate Alzheimer's disease be not to interact with the HSP90 path to estrogen through acting on the phospholipid metabolism process.There is document to point out that estrogen can reduce the ill risk of Alzheimer's disease through the generation of anti-beta-amyloyd body.And estrogen quickens transporting goods for sale of β APP through the level of regulating TGN phosphatide and prevent the generation of A β.Therefore, Fulvestrant as the antagonist of an ERs, acts on the beta-amyloyd body through the phosphatide path and increases the weight of Alzheimer's disease.Therefore, 1) the ERs path possibly alleviate the Alzheimer disease through phosphatide.2) the HSP90 suppressant is not relevant with Alzheimer's disease through acting on mutually with estrogen pathway.3) ERs possibly be a good target spot of treatment Alzheimer's disease.
All documents in that the present invention mentions are all quoted as a reference in this application, are just quoted such as a reference separately as each piece document.Should be understood that in addition after having read above-mentioned teachings of the present invention, those skilled in the art can do various changes or modification to the present invention, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Claims (10)
1. stride the method that species are analyzed the latent effect of medicine to be measured for one kind, it is characterized in that, comprising:
(1) gene expression profile of acquisition testing group and control group; This testing group is the animal disease model after the drug-treated to be measured; This control group is not with the animal disease model of drug-treated to be measured;
(2) with the conversion of the dna homolog in the gene expression profile of the animal disease model of (1) adult's homologous gene, thereby the gene in the gene expression profile of animal disease model is converted into people's homologous gene, obtains corresponding people's homologous gene and expression;
(3) testing group and the homogenic expression of control group people are compared, remove the inapparent part of differential expression in the testing group; The significant people's homologous gene of differential expression in the testing group is carried out the enrichment analysis of gene ontology module, obtain the gene ontology module of significant difference;
(4) express spectra before and after various known drugs are handled of this kind of collection disease association from reference database is handled the express spectra of front and back to each known drug, and the significant gene of collection and treatment front and back differential expression carries out the enrichment analysis of gene ontology module; Thereby,, obtain the gene ontology module of one group of significant difference to each known drug;
(5) (3) the gene ontology module that obtains and each group gene ontology module that (4) obtain carried out similarity relatively; Quantity according to similarity gene module is carried out rank to corresponding known drug (like micromolecular compound) in the reference database; Similarity gene module number is relevant more more at most; Confirm maximally related several medicines, they are and the immediate known drug of pharmic function to be measured, thereby learn the latent effect of medicine to be measured.
2. an analysis to disease animal model effectively or the method for pathogenic potential drug is arranged is characterized in that this method comprises:
(1) gene expression profile of acquisition testing group and control group; This testing group is the animal model under the morbid state; This control group is the animal model under the health status;
(2) with the conversion of the dna homolog in the gene expression profile of the animal disease model of (1) adult's homologous gene, thereby the gene in the gene expression profile of animal model is converted into people's homologous gene, obtains corresponding people's homologous gene and expression;
(3) testing group and the homogenic expression of control group people are compared, remove the inapparent part of differential expression in the testing group; The significant people's homologous gene of differential expression in the testing group is carried out the enrichment analysis of gene ontology module, obtain the gene ontology module of significant difference;
(4) express spectra before and after various known drugs are handled of this kind of collection disease association from reference database is handled the express spectra of front and back to each known drug, and the significant gene of collection and treatment front and back differential expression carries out the enrichment analysis of gene ontology module; Thereby,, obtain the gene ontology module of one group of significant difference to each known drug;
(5) (3) the gene ontology module that obtains and each group gene ontology module that (4) obtain carried out similarity relatively; Quantity according to similarity gene module is carried out rank to corresponding known drug (like micromolecular compound) in the reference database, and similarity gene module number is relevant more more at most;
(6) confirm maximally related several medicines, they are that disease animal model is had pathogenic potential drug; Confirm several least relevant medicines, they are to the effective potential drug of this disease.
3. according to claim 1 or claim 2 method is characterized in that in (4), described reference database is mainly derived from Connectivity Map, and it has been put down in writing between various medicine-diseases and has got in touch, and the express spectra before and after the drug-treated.
4. according to claim 1 or claim 2 method is characterized in that described medicine to be measured is compound (like a micromolecular compound).
5. according to claim 1 or claim 2 method is characterized in that, in (2), carries out the homology conversion through Roundup homologous gene database.
6. according to claim 1 or claim 2 method is characterized in that, in (3), the threshold value of differential expression is set, and shows that difference is not remarkable, shows significant difference and be higher than this threshold value if be lower than this threshold value.
7. method as claimed in claim 6 is characterized in that, the threshold value of this differential expression is 2 times of differential expressions.
8. according to claim 1 or claim 2 method is characterized in that, in (3), the method for utilizing the hypergeometry check is carried out the enrichment analysis of gene ontology module to people's homologous gene of the significant difference picked out.
9. according to claim 1 or claim 2 method is characterized in that, in (5), adopts the similarity of Kolmogorov-smirnov algorithm computation gene ontology module.
10. according to claim 1 or claim 2 method is characterized in that said method also is used for:
The same or analogous medicine of enrichment function; Or
Well whether the assessment animal disease model anthropomorphic dummy's disease.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110126461.XA CN102789550B (en) | 2011-05-17 | 2011-05-17 | A kind of element method utilized across species similarity |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201110126461.XA CN102789550B (en) | 2011-05-17 | 2011-05-17 | A kind of element method utilized across species similarity |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102789550A true CN102789550A (en) | 2012-11-21 |
| CN102789550B CN102789550B (en) | 2015-11-25 |
Family
ID=47154953
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201110126461.XA Expired - Fee Related CN102789550B (en) | 2011-05-17 | 2011-05-17 | A kind of element method utilized across species similarity |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102789550B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107075510A (en) * | 2014-10-17 | 2017-08-18 | 皇家飞利浦有限公司 | The cross-platform conversion of gene expression data |
| CN113436729A (en) * | 2021-07-08 | 2021-09-24 | 湖南大学 | Synthetic lethal interaction prediction method based on heterogeneous graph convolution neural network |
| CN116705175A (en) * | 2023-06-08 | 2023-09-05 | 南京农业大学 | Cross-species comparative genomics database and construction and analysis method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110015869A1 (en) * | 2008-03-22 | 2011-01-20 | Merck Sharp & Dohme Corp | Methods and gene expression signature for assessing growth factor signaling pathway regulation status |
| CN101989297A (en) * | 2009-07-30 | 2011-03-23 | 陈越 | System for excavating medicine related with disease gene in computer |
-
2011
- 2011-05-17 CN CN201110126461.XA patent/CN102789550B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110015869A1 (en) * | 2008-03-22 | 2011-01-20 | Merck Sharp & Dohme Corp | Methods and gene expression signature for assessing growth factor signaling pathway regulation status |
| CN101989297A (en) * | 2009-07-30 | 2011-03-23 | 陈越 | System for excavating medicine related with disease gene in computer |
Non-Patent Citations (3)
| Title |
|---|
| TODD F.DELUCA ET AL.: "Roundup: a multi-genome repository of orthologs and evolutionary distances", 《BIOINFORMATICS》, vol. 22, no. 16, 15 June 2006 (2006-06-15) * |
| 吴爱明: "活血益气方药改善心梗气虚血瘀大鼠模型心肌损伤和CX43的研究", 《中国优秀硕士学位论文全文数据库医药卫生科技辑》, no. 12, 15 December 2010 (2010-12-15), pages 057 - 66 * |
| 韩清民等: "补肾方对肾虚型大鼠膝骨关节炎软骨病变基因表达谱的影响", 《中国组织工程研究与临床康复》, vol. 12, no. 46, 11 November 2008 (2008-11-11) * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107075510A (en) * | 2014-10-17 | 2017-08-18 | 皇家飞利浦有限公司 | The cross-platform conversion of gene expression data |
| CN107075510B (en) * | 2014-10-17 | 2021-03-23 | 皇家飞利浦有限公司 | Cross-platform transformation of gene expression data |
| CN113436729A (en) * | 2021-07-08 | 2021-09-24 | 湖南大学 | Synthetic lethal interaction prediction method based on heterogeneous graph convolution neural network |
| CN116705175A (en) * | 2023-06-08 | 2023-09-05 | 南京农业大学 | Cross-species comparative genomics database and construction and analysis method thereof |
| CN116705175B (en) * | 2023-06-08 | 2023-12-29 | 南京农业大学 | Cross-species comparative genomics database and construction and analysis method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102789550B (en) | 2015-11-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Martos et al. | Memory enhancement with kynurenic acid and its mechanisms in neurotransmission | |
| Orlando et al. | Mesoporous silica nanoparticles trigger mitophagy in endothelial cells and perturb neuronal network activity in a size-and time-dependent manner | |
| Zhang et al. | Direct inhibition of the TLR4/MyD88 pathway by geniposide suppresses HIF‐1α‐independent VEGF expression and angiogenesis in hepatocellular carcinoma | |
| Davoudian et al. | Shared and distinct brain regions targeted for immediate early gene expression by ketamine and psilocybin | |
| Carrasco et al. | Cancer stem cells and their implication in breast cancer | |
| Ban et al. | Hypoxia-inducible factor (HIF) inhibitors: a patent survey (2011-2015) | |
| Su et al. | Targeting Src reactivates pyroptosis to reverse chemoresistance in lung and pancreatic cancer models | |
| Källstig et al. | The Links between ALS and NF-κB | |
| Martinez et al. | Drugs in clinical development for the treatment of amyotrophic lateral sclerosis | |
| Williams et al. | Therapeutic anticancer efficacy of a synthetic diazonamide analog in the absence of overt toxicity | |
| Thariat et al. | Hadrontherapy interactions in molecular and cellular biology | |
| Reis et al. | Epoxylathyrane derivatives as MDR-selective compounds for disabling multidrug resistance in cancer | |
| Busonero et al. | Ouabain and digoxin activate the proteasome and the degradation of the ERα in cells modeling primary and metastatic breast cancer | |
| Zeng et al. | Salidroside promotes sensitization to doxorubicin in human cancer cells by affecting the PI3K/Akt/HIF signal pathway and inhibiting the expression of tumor-resistance-related proteins | |
| Ali et al. | Amomum subulatum: a treasure trove of anti-cancer compounds targeting TP53 protein using in vitro and in silico techniques | |
| CN102789550A (en) | Meta-analysis method utilizing cross-species similarity | |
| Shi et al. | Molecular and metabolic mechanisms of bufalin against lung adenocarcinoma: New and comprehensive evidences from network pharmacology, metabolomics and molecular biology experiment | |
| Munro | Bystander effects and their implications for clinical radiotherapy | |
| Guo et al. | Huperzine A injection ameliorates motor and cognitive abnormalities via regulating multiple pathways in a murine model of Parkinson's disease | |
| Ji et al. | Efficacy of bronchoscopic intratumoral injection of endostar and cisplatin in lung squamous cell carcinoma patients underwent conventional chemoradiotherapy | |
| Wang et al. | Exploration of the potential mechanism of Qi Yin San Liang San decoction in the treatment of EGFRI-related adverse skin reactions using network pharmacology and in vitro experiments | |
| Ling et al. | Exploration of the effect of Celastrol on protein targets in nasopharyngeal carcinoma: Network pharmacology, molecular docking and experimental evaluations | |
| Chao et al. | Deep Learning‐Assisted Repurposing of Plant Compounds for Treating Vascular Calcification: An In Silico Study with Experimental Validation | |
| Lamkin et al. | Translating preclinical research for exercise oncology: take it to the VO2max | |
| Wang et al. | Interpreting the pharmacological mechanisms of sho-saiko-to on thyroid carcinoma through combining network pharmacology and experimental evaluation |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CP03 | Change of name, title or address | ||
| CP03 | Change of name, title or address |
Address after: 200031 Yueyang Road, Shanghai, No. 319, No. Patentee after: Shanghai Institute of nutrition and health, Chinese Academy of Sciences Address before: 200031 No. 320, Yueyang Road, Shanghai Patentee before: SHANGHAI INSTITUTES FOR BIOLOGICAL SCIENCES, CHINESE ACADEMY OF SCIENCES |
|
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20151125 Termination date: 20200517 |