Re: AD Use Case

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 - William.Bug@DrexelMed.edu