Hi All,
I think Alan is getting at the right point here, but there is both a
BioRDF component task, as well as a BioONT component task involved here.
Sorry for digging a little into the biology here, but as we discussed
during the final manuscript review of the AD Use Case, ADDL is the
acronym for Amyloid-beta Derived Diffusible Ligands (PMID:
16712494). ADDL represent a set of proteolytic products derived from
Amyloid-beta transciption products. I believe neither of the
following are clear yet:
1) what ALL the ADDL peptides are
2) from which Abeta splice product (PMID: 7499323) they all derive
(the use case currently discusses > 1 - though it focusses on A-beta*56)
3) exactly which ADDL ligand(s) are responsible for AD related
symptomotology
4) exactly how ADDL expression in humans with AD and in AD mouse
models compare.
The goal is to test the ability of an anti-ADDL antibody to to
"clear" this toxic APP proteolytic product from the patient's CSF and
brain parenchyma.
June & Gwen can help us vet what I've stated above. In particular, I
believe from what June mentioned recently, it is believed a SPECIFIC
individual ADDL ligand is of primary importance - and it is THIS
PARTICULAR ligand many reports refer to when using the label ADDL.
As folks may know, a single type of IGG antibody binds to a specific
epitope - a defined biochemcial subdomain or moeity within a
particular molecule. It is possible for a single molecule to have
more than one moeity to which you can raise a specific IGG.
Antibodies are generally derived either as a clonal population from a
single activated B-Cell (monoclonal antibodies)**, or one can do
bleeds of an immunized animal to derive IGG regeants to a cornucopia
of epitopes (polyclonal sera). Depending on the length of the peptide
and the general chemical nature of its many biochemical subdomains, a
given peptide immunogen may give rise to polyclonal sera with a very
diverse set of IGGs.
In order to be effective at clearing a peptide, it's probably the
case a polyclonal sera binding to multiple epitopes on the culprit
peptide would be required. If the specific peptide is known, that
peptide can be used to affinity-purify (or affinity-mature) the
polyclonal sera, even if a combination of peptides from the ADDL set
is used to raise the sera. A patent has actually been filed on this
very procedure (http://www.freepatentsonline.com/20060228349.html),
which is not surprising given what June has said regarding the
maturing understanding of the specific ligand in the ADDL set that
appears to be the most toxic.
This is some of the methodological detail we'll need to track to
SPECIFICALLY address the issue of Immunotherapy efficacy. As to the
toxicity issue, we'd need to be able to include relevant cytokines,
growth factors, and cellular immuno entities identified in the course
of the toxicity reports.
OK - I only went into that detail to given the following follow-up to
Alan's comment.
There are instance-level entities (BioRDF), as well as Distilled
Knowledge Resource entities (BioONT). Below I list a subset of each.
The specific MeSH entries you see below (again - just a subset of
what is in MeSH for Abeta fragments) would need to be linked in a
collection of triplets to ADDL:
:ADDL :has_part :MeSH:67514245
:ADDL :has_part :MeSH:67512364
:ADDL :has_part :MeSH:67511651
:anti-Abeta(1-42) :binds_epitope_on :MeSH:67514245
:anti-Abeta(29-42) :binds_epitope_on :MeSH:67512364
BioRDF (We need to identify the use of all Distilled Knowledge
Sources across these repositories for BioONT to correlate):
NUCLEOTIDE SEQUENCE:
APP transcripts
GI:118130287
GI: 85861185
...
...
Genomic cloned sequence containing APP CDS
GI:34221844
GI:18121459
...
...
PROTEIN SEQUENCE
GI:41406057
GI:47271504
...
...
PROTEIN STRUCTURE
Abeta(1-42) - soluble
PDB: 1Z0Q
Abeta(1-42) fibrils
PDB: 2BEG
GENSAT
beta-site, APP-cleaving enzyme 2 (GENSAT: 51947)
OMIM
APP - OMIM: 104760
Possibly Also:
AlzForum: Antibody Directory
http://www.alzforum.org/res/com/ant/default.asp
Antibody Dtb - http://www.antibodyresource.com/
- may not be sufficiently open to be useful to us - AlzForum links
to it, so they will know
ExactAntigen - http://bin.exactantigen.com
- many relevant hits
MSRS Catalog of Primary Antibodies -
http://www.antibodies-probes.com/
- several relevant hits - but requires sub
BioONT:
MeSH:
Abeta(1-42) (MeSH: 67514245)
Abeta(29-42) (MeSH: 67512364)
Abeta(10-21) (MeSH: 67511651)
...
...
Possibly:
the Immunology Ontology component of the ImmPort System
-
https://www.immport.org/immportWeb/display.do?content=AboutImmPort
- they are also contributing immuno methodological entities to the
Ontology of Biomedical Investigation
Cheers,
Bill
**Many many moons ago, I took the CSH summer course co-taught by
MIT's now president, Sue Hockfield - "Raising Monoclonal Antibodies
to Neural Antigens"
On Jan 21, 2007, at 4:06 PM, Alan Ruttenberg wrote:
Hi June,
The issue wasn't legal use - rather I was trying to point out that
there aren't public databases that include ADDLs that I was aware of.
So unlike a gene, which we could identify by a URI based on the
Entrez Gene id, I don't know of an analogous resource to identify
ADDLs. This is probably a job for BioONT - either identify an
existing ontology that includes ADDLs, or generate an ontology that
we could use. In some sense this isn't a technical issue in using
the data for the demo, as much as demonstrating how all of it
places in the larger semantic web.
Best,
Alan
On Jan 21, 2007, at 3:52 PM, June Kinoshita wrote:
I think it would be OK to use the antibody date if we include the
source/credit tag as agreed upon.
June
On Jan 21, 2007, at 9:59 AM, Tim Clark wrote:
Alan,
DS1 can be provided from SWAN beta which we expect to have out by
then. At minimum we would give the RDF representation from
SWAN. Right June?
Tim
On SundayJan 21, 2007, at 2:33 AM, Alan Ruttenberg wrote:
I, among others, took the action item to review the AD use case
and associated data sets. Summary: 7 data sets listed. 2 are
freetext/difficult to convert/query. Wasn't sure how 1 was to be
used. 1 (antibody) has identifier issue for this case. 3 look
usable as specified.
Please chime in to correct errors, fill in details.
Regards,
Alan
In our use case, an investigator reads about the discovery of a
new form of Abeta, called Abeta*56, that is reported to cause
memory impairment in a mouse model of AD. (DS1 - Alzheimer
Research Forum News)
It isn't clear in what sense DS1 is a data set to be used in the
use case. Are we expecting that DS1 is to be represented as RDF?
If so, this is something of a challenge, as it is primarily free
text.
Question: Is there human data to support that Abeta*56 is
involved.
A query of PubMed (DS2 - PubMed) finds a paper reporting that a
form of Abeta with identical molecular weight, called ADDL, is
elevated by as much as 70-fold in human AD patients'
cerebrospinal fluid. A hypothesis about ADDL causing memory
loss in AD is posted on Alzforum.
I'm not sure how to encode pubmed (free text + mesh terms) in
such a way as to successfully make this query. The pmids for the
papers cited in the HCLSIG paper, and their searchable
annotations are below. I've condensed this from the XML
representation of the record, specifically the <ChemicalList >,
and the <MeshHeadingList>. To do this query the annotations
would at least have to mention something to do with memory
impairment and Abeta*56, which neither do.
PMID:15695586
Chemical: Amyloid beta-Protein, Biological Markers, Ligands, DNA
Topic:Alzheimer Disease, *cerebrospinal fluid,diagnosis,genetics
Topic:Amyloid beta-Protein,*cerebrospinal fluid,genetics,
Topic:Base Sequence
Topic:Biological Markers,cerebrospinal fluid
Topic:Case-Control Studies
Topic:DNA,genetics
Topic:Humans
Topic:Ligands
Topic:Nanotechnology
Topic:Polymerase Chain Reaction,methods,statistics & numerical data
Topic:Sensitivity and Specificity
Topic:Solubility
PMID: 9163350
Chemical: Amyloid,Nerve Tissue Proteins,Protein Precursors,
SNCA protein- human,SNCB protein- human,Synucleins,alpha-
Synuclein,
beta-Synuclein,Biotin
Mesh:Amyloid,*metabolism
Mesh:Binding Sites
Mesh:Biotin
Mesh:Electrophoresis, Polyacrylamide Gel
Mesh:Humans
Mesh:Nerve Tissue Proteins,*metabolism
Mesh:Protein Precursors,*metabolism
Mesh:Spectrometry, Mass, Matrix-Assisted Laser Desorption-
Ionization
Mesh:Synucleins
Mesh:alpha-Synuclein
Mesh:beta-Synuclein
Question: By what mechanism might Abeta*56 cause memory loss?
The ADDL Hypothesis on Alzforum suggests that ADDL (=
Abeta*56?) disrupts LTP.
I think we have to parse free text to determine this. I don't
know ho
Question: What is the mechanism of LTP, in a part of the brain
that is relevant to AD?
The literature indicates CA1 hippocampal neurons, and A- and D-
type K channels are involved in LTP. BrainPharm (DS3 - Senselab
BrainPharm) data state that CA1 hippocampal neurons have A-
channels. What's more, the A-current is reduced by Abeta.
Verified(second sentence): http://senselab.med.yale.edu/senselab/
BrainPharm/alzData.asp
Question: Would an antibody directed against ADDL / Abeta*56
restore A-current in the mouse model hippocampal neuron (e.g.
in an organotypic slice prep)?
A query locates an antibody (DS4 - Alzheimer Research Forum
Antibody Database) to ADDL and where to obtain it.
Could search here by name, and succeed. However ADDL isn't an
entity that is given an identifier in any of the standard
databases I am aware of, so we do have an issue to deal with
here. Antibody db conversion focuses on proteins whose gene ids
can be found.
Our investigator queries pathway databases to identify the gene
network involved in IFNG regulation, and also SNP databases for
differences between mouse strains, mouse and human (DS5 -
GeneNetwork, DS6 - KEGG). He narrows down a group of genes and
queries the AlzGene (DS7 - AlzGene) database to see if any gene
association studies have shown a correlation between any of
these genes and AD risk.
Verified(IFNG): Could start here for interferon gamma, which
links to several pathways in KEGG. http://www.genome.jp/dbget-
bin/www_bget?hsa+3458
Wasn't sure how to use GeneNetwork. Verified that Alzgene links
Gene/SNP to association study.
Bill Bug
Senior Research Analyst/Ontological Engineer
Laboratory for Bioimaging & Anatomical Informatics
www.neuroterrain.org
Department of Neurobiology & Anatomy
Drexel University College of Medicine
2900 Queen Lane
Philadelphia, PA 19129
215 991 8430 (ph)
610 457 0443 (mobile)
215 843 9367 (fax)
Please Note: I now have a new email - [EMAIL PROTECTED]
