View source for MarathonMouseUseCase

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The overall story: The PPARD agonist GW501516 is in Phase II trials for dyslipidemias.  It was recently shown to have a remarkable effect on mice, making them able to run twice as far as controls, and making them resistant to the obesigenic effects of high fat diets.  This is of course, one of the great outstanding markets left for blockbuster drugs: Imagine, the benefits of exercise in a pill! Of course, no drug is without problems, and PPAR-related compounds generally have some scarey toxicity problems, particularly around cancer.  

This story can be told from several perspectives:

* Business:  who has a financial interest in the compound, what are the issues with respect to its path toward FDA approval, what are the competitors. 
* Genetics: information about the target, PPARD.  The various human   subtypes and polymorphisms.  Relationship between human PPARD and  mouse (where most of the studies have been done).  Role in normal   biology (in addition to its fat-related effects, it plays a role in development, inflamation and possibly neurological activity). 
* Toxicity: PPARD agonists have increased growth rates of certain kinds of cancer cell lines, and the FDA has special guidelines for showing  that PPAR-related compounds are not carcinogenic.

1 Basic information about the gene and the drug(s)

* Formal gene name: peroxisome proliferative activated receptor, delta  Symbol: PPARD  ''NB: there are naming problems -- generally PPAR beta is the same same as delta.  Also note there are two human isoforms (although not two mouse isoforms).''
* The ppard agonists (potential drugs) are currently called GW0742 and GW501516.  These are very closely related compounds (just a single atom difference between them). Here is an article that 
 [http://www.sigmaaldrich.com/img/assets/6780/PPARS.pdf describes their structures]. It would be really nice to be able to extract these structures from the article and get them in RDF form.

2 Literature searches of [http://www.ncbi.nlm.nih.gov/PubMed pubmed] for (ppard or "ppar delta") yields 77 articles.  A search on GW501516 gives 11 articles.  The key articles are: 

  2.1 The [http://www.plosbiology.org/plosonline/?request=get-document&doi=10.1371/journal.pbio.0020294 "Marathon Mouse" article itself] (including videos of the mice). [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Display&dopt=pubmed_pubmed&from_uid=15328533 98 related articles] as found by the Pubmed "related articles" link.

  2.2 The [http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=33205 initial publication of the agonist GW501516], on the cholesterol indication. The [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Link&dbFrom=PubMed&from_uid=11309497 107 related articles] from Pubmed "related articles".  Question: what is the overlap between the related articles here and the related articles in 2.1, and which of those (if any) do not appear in the original searches on PPARd and GW501516?

  2.3 A [http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=307669 lipid response study of GW501516] using Affy arrays.  The raw data is [http://www2.genome.rcast.u-tokyo.ac.jp/PNASL6/ here].  NB: this expression array data is not submitted to a public repository, but is served off the [http://www.lsbm.org/site_e/database/index.html LSBM web site].  Table 1 of [http://www2.genome.rcast.u-tokyo.ac.jp/PNASL6/PNASL6_tanaka_supporting.pdf the supporting information] for that publication is also pretty interesting.  Could it be extracted from the PDF and represented in RDF?

  2.4  Two articles ([http://www.nature.com/cgi-taf/DynaPage.taf?file=/nm/journal/v10/n4/abs/nm1025.html&dynoptions=doi1088789835 one] [http://diabetes.diabetesjournals.org/cgi/content/full/53/3/847 two]) about PPARD's role in obesity.

  2.5 Its [http://www.pubmedcentral.nih.gov/articlerender.fcgi?pubmedid=12756292 role in inflamation].

  2.6 A [http://www3.interscience.wiley.com/cgi-bin/fulltext/108566886/PDFSTART hint of a role of PPARd] (called here PPARb) in neurological disorders

  2.7 A big issue is whether PPARd plays a role in causing or promoting cancer or has other toxicities.  Here are four articles on various aspects of that question: [http://www.nature.com/cgi-taf/DynaPage.taf?file=/nrc/journal/v4/n3/full/nrc1304_fs.html a nice summary] [http://www.nature.com/doifinder/10.1038%2Fnrc1254 two] [http://www.nature.com/cgi-taf/DynaPage.taf?file=/nm/journal/v10/n3/abs/nm993.html&dynoptions=doi1088789761 three] [http://cancerres.aacrjournals.org/cgi/content/full/64/9/3162 four]

  2.8 Here are two articles about PPARd related drugs and how to synthesize them.  The data in the tables of [http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6TF9-487TV9P-3-7&_cdi=5221&_orig=search&_coverDate=05%2F05%2F2003&_qd=1&_sk=999869990&view=c&wchp=dGLbVlz-zSkWb&_acct=C000019840&_version=1&_userid=418620&md5=39312c9ab7e5c354188001e2c44963bd&ie=f.pdf  the first] would be very valuable.  [http://pubs.acs.org/cgi-bin/article.cgi/joceah/2003/68/i23/pdf/jo035140g.pdf the second] is also interesting. 

3. Databases to integrate.  There is information about PPARd in many publically available databases.  Most of this data is linked to from NCBI's Entrez Gene entry (see 3.1). Data sets not accessible through links from NCBI are '''highlighed.'''

 3.1  The[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=5467 Entrez Gene entry] and the [http://us.expasy.org/cgi-bin/niceprot.pl?Q03181 UniProt entry]

 3.2 Refseq entries [http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=Nucleotide&dopt=GenBank&val=29171748 isoform 1 nucleotide] [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?dopt=GenPept&cmd=Retrieve&db=protein&list_uids=5453940 isoform 1 protein] [http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=Nucleotide&dopt=GenBank&val=29171749 isoform 2 nucleotide] [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?dopt=GenPept&cmd=Retrieve&db=protein&list_uids=29171750 isoform 2 protein]

 3.3 The [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=homologene&dopt=HomoloGene&list_uids=4544 homologene report]

 3.4 The [http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?locusId=5467 NCBI polymorphisms].  I would like to find other polymorphisms, since these differences should explain the naturally occurring differences among people.  ''' [http://egp.gs.washington.edu/data/ppard/ Here] is the [http://egp.gs.washington.edu/ NIEHS snp data].  And here is [http://www.genome.utah.edu/genesnps/cgi-bin/frame.cgi?gene_id=361 some more PPARd snp data] from [http://www.genome.utah.edu/genesnps/ Utah's Gene SNPs project].  And now [http://receptors.ucsf.edu/NR/mutation/Rec_page/PPAS_HUMAN.mut.html four mutations] automatically extracted from the literature by [http://receptors.ucsf.edu/NR/ the NucleaRDB project]. '''

 3.5 '''The [http://bioinfo.weizmann.ac.il/cards-bin/carddisp?PPARD&search=ppard&suff=txt GeneCards entry] summarizes data from other databases.  It's particularly interesting for the tissue distribution data.'''

 3.6 Not only is the structure of the protein known, but we have a [http://pdbbeta.rcsb.org/pdb/explore.do?structureId=3gwx structure of it bound to its ligand!]

 3.7 Here is the [http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600409 OMIM entry] which both provides a nice summary of what is known about the gene and a description of its known role in various diseases.

 3.8 Here is the [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=gene&cmd=Display&dopt=gene_geo&from_uid=5467 summary page] for records in the GEO database of expression array data relevant to PPARd.   Some datasets of particular interest include three on fat metabolism: [http://www.ncbi.nlm.nih.gov/geo/gds/gds_browse.cgi?gds=158 one] [http://www.ncbi.nlm.nih.gov/geo/gds/gds_browse.cgi?gds=156 two] [http://www.ncbi.nlm.nih.gov/geo/gds/gds_browse.cgi?gds=596 three].

 3.9 '''Here is the [http://genome.ucsc.edu/cgi-bin/hgTracks?Submit=Submit&position=NM_177435 UCSC Genome Browser entry]  Many tracks (and corresponding aspects of the underlying database) are of potential interest here.  For example,  regions upstream of the gene that is conserved between mouse and human (a track) would be a particularly interesting place to look for human polymorphisms (another track) because those might suggest regulatory polymorphisms among individuals that would explain individual human differences.'''

 3.10 There isn't very much pathway data that I could find. [http://www.genome.jp/dbget-bin/show_pathway?hsa04310+5467 KEGG shows it is a downstream responder in the WNT pathway].  '''The [http://cgap.nci.nih.gov/Genes/GeneInfo?ORG=Hs&CID=106415 CGAP entry] has pointers to better pathway data from Biocarta: [http://cgap.nci.nih.gov/Pathways/BioCarta/h_pparPathway ppar pathways] and [http://cgap.nci.nih.gov/Pathways/BioCarta/h_nuclearRsPathway lipid metabolism / toxicity pathways].'''

 3.11 '''The [http://www.signaling-gateway.org/molecule/query?afcsid=A001887 signaling gateway entry] doesn't offer pathways, but does have links to [http://bind.ca/Action?idsearch=gi:5453940 bind protein-protein interactions].'''

 3.12 '''[http://www.informatics.jax.org/javawi2/servlet/WIFetch?page=markerDetail&key=17756 Here] is the PPARd information from the MGI database (in html format).'''  [ftp://ftp.informatics.jax.org/pub/ADHOCSERVER Here is general information] about access through the  MGI SQL server.  Ian sent around access passwords, etc. via email.  

4. Business links (how to find these?  Google?)

 4.1  The [http://www.corporate-ir.net/ireye/ir_site.zhtml?ticker=LGND&script=410&layout=-6&item_id=581138 compound is owned] by [http://www.ligand.com/ Ligand] and licensed to GSK. Among many other places, financial information about the company ( nasdaq:LGND ) can be found [http://cbs.marketwatch.com/tools/quotes/quotes.asp?symb=LGND&siteid=mktw&dist=mktwqn here].  I imagine there are better sources of RDF business information out there.

 4.2 The FDA is particularly concerned about safety of PPAR-related compounds, and has published [http://www.fda.gov/cder/present/DIA2004/elhage_files/frame.htm specific safety standards just for PPAR compounds].