Transcript Slide 1

Animal Models in Clinical and
Translational Science
Navigating the Translational Researcher
Through a Complex of
Animal and Biological Resources
NCRR
March 6-7, 2006
Keith C. Cheng, MD, PhD
Jake Gittlen Cancer Research Foundation
Penn State College of Medicine
[email protected]
Topics









Audiences and functionalities
Animal Models: Model Systems
Biological Processes/Diseases
Linking Concepts between web sites
Systems Morphogenetics
Answering and Raising Questions
Examples of Model System, Process,
Disease
Quality of Information
Accessibility of information
Audience



Clinician Scientists
Translational Researchers
Basic Scientists
Audience: Who’s at the bedside?





Clinician Scientists
Translational Researchers
Basic Scientists
Clinicians*
Public



Patients*
General Public
Students






PhD trainees
MD trainees
College Students
HS Students
Middle School Students
Legislators
Audience Functionalities




One-stop shopping
Engender thinking processes (genetics/reverse
genetics)
Feedback
For new researchers:




“Nice model but how does that help the patient?”
“Nice model, but in what ways is the model different from
the range of human disease?
“What are the limitations of the model?”
“What would another ideal model do that current ones
don’t?”
Animal Models: The obvious

Vertebrates




Primates
Mice
Rats
Zebrafish
Animal Models: Others

Invertebrates



Single Cell Organisms




Flies
Worms
Phage
Bacteria
Yeast
Other models





Xenopus
Dogs
Tetrahymena
Other fish: Fugu/Medaca/Xiphophorus
Hydra
Animal Model: Man!









Anatomy
Histology
Physiology
Genetics
Gene expression
Disease
Correlations with animal models
Environment
Psychosocial issues
Biological Process/Disease







Aging
Normal Variation
Neurophysiology
Cancer
Pigmentation
Metabolism
Infectious Disease
Linking Concepts









Biochemical and Signal Transduction
Pathways
Genes
Gene Expression
Anatomy
Histology
Subcellular localization
Life Span
Physiology
Disease
Linking Concept: Comparisons





Wild type vs. mutant or morphant
Older vs. Younger
Treated vs. untreated
One organism vs. another
Multilevel





Organ
Tissue
Cell
Subcellular
Molecular
An example of gene comparisons: human polymorphism
rs1426654 affects a conserved amino acid
conserved C
F P
(NCKX)
conserved CD YFLPSLE I
(NCKX5)
L
DVA ATFMA
PE
LGLSQDVAGATFMA GSSAPE VT FLG
zf5
CDEYFLPSLEVISERLGLSQDVAGATFMAAGSSAPELVTAFLG
medaka5
CDDYFLPSLEVISERLGLSQDVAGATFMAAGSSAPELVTAFLG
fugu5
CDDYFLPSLEVISERLGLSQDVAGATFMAAGSSAPELVTAFLG
Xentrop5
CESYFIPSLEVISERLGLSQDVAGATFMAIGSSAPEFVTVFLG
chk5
CDDYFLPSLEIITECLGLSQDVAGATFMAAGSSAPELVTAFLG
dog5
CDEYFLPSLEIISETLGLSQDVAGATFMAAGSSAPELVTAFLG
cow5
CDEYFLPSLEIISESLGLSQDVAGATFMAAGSSAPELVTAFLG
mu5
CDKYFLPSLEIISDSLGLSQDVAGATFMAAGSSAPELVTAFLG
rat5
CDKYFLPSLEIISDSLGLSQDVAGATFMAAGSSAPELVTAFLG
hunckx5
CDEYFLPSLEIISESLGLSQDVAGATFMAAGSSAPELVTAFLG
(YRI/HCB/JPT)
hunckx5
CDEYFLPSLEIISESLGLSQDVAGTTFMAAGSSAPELVTAFLG
(CEU)
Victor Canfields
The zebrafish golden
phenotype
golb1/golb1
wild-type
48 hpf
72 hpf
Becky Lamaso
Diminished melanosome
morphogenesis in golden skin
Greg Ning
Comparison within a genome:
Regional homozygosity in Europeans (CEU)
Wei Zhao, Adam Sidor, Joe Gershenson, Victor Canfield, Jason Mest
Comparison between genomes: Diminished
regional heterozygosity near SLC24A5
Comparison between populations:
SLC24A5 rs1426654 allele frequencies
Population
European American, Utah (CEPH)
European American, Baltimore
European American, Chicago
European Total
Japanese, Toky o
Cantonese, China
Han Chinese, Beijing
East Asian Total
Zapotec, Mex ico
I ndigenous American Total
Yoruba, I badan, Nigeria
Ghana, West Africa
Cameroon, West Africa
Senegal, West Africa
Botswana, West Africa
African Total
Thr (A) allele
frequency
Sample
size
Ref
1.0
0.987
0.987
0.992
0.011
0.012
0.011
0.012
0.069
0.069
0.025
0.000
0.000
0.065
0.048
0.030
59
39
39
127
44
40
45
129
29
29
60
33
20
46
21
180
1
2
2
1
2
1
2
1
2
2
2
2
1 www.HapMap.org
2 M. W. Smith et al, 2004
Systems Morphogenetics






Where
When
Why (function)
Physiology
Disease
Response to treatments



Therapeutic
Side-effects
Rare adverse responses
Answering Questions

Function*
Mutants
 Knock-downs
 Disease






Pathway
Tissue specificity
Subcellular localization
Age specificity
Downstream effects
Raising Questions






What we don’t know
Important to direct questions
Prioritization
Identification of information with degrees
of uncertainty
Identify information of conflicting opinion
Highlighting of important unknowns,
clinical problems and clinical goals
Animal Model Example:
Zebrafish





Development
Disease (cancer, infectious disease, etc)
Drug development
Toxicology
Bridge organism between invertebrates and
mammals
Disease Example: Cancer







Models span yeast to humans
Many diseases
Many different pathophysiologies
Complicated genetics
Primitive treatments
Genomic instability creates moving target
Cancer genome anatomy project
Process Example: Pigmentation






Different genes important in different settings
Most common variations affecting color
Skin vs. hair vs. eye
Two to three most important
Many genes modulate
Other potential effects:




Parkinson’s Disease
Age-related macular degeneration
Frostbite susceptibility
“Solvable” problem
Pigmentation

Variable anatomy/histology









Distribution of pigmented cells
Variable pigment
Transfer of pigment between cells
Variable biochemistry (eumelanin vs pheomelanin)
Variations in melanosome morphology
Proteomics coming online
Extensive genetics
Extensive evolutionary conservation of function
Diseases: cancers, normal and abnormal patterns,
normal and abnormal pigmentation
Quality of Information: We must
reach for the ideal, but much is…





Inaccurate
Incomplete
Misleading
Uncertain
Limited
“No similarity-to-human data found for SLC24A5 in HomoloGene
for: Pan troglodytes, Sus scrofa, Bos taurus, Danio rerio . . .”
– source: <http://genome-www.stanford.edu/cgibin/genecards/carddisp?SLC24A5>
•Website updated on
1/20/2006
•Incorrectly cites expression
and subcellular localization
data
•States nervous and
cone photoreceptor
expression only
•States plasma
membrane localization
•We have shown
ubiquitous expression in
adults (higher in
pigmented tissues)
•We have shown
subcellular localization
to an internal organelle
•Cites SNP data from paper,
but ignores expression data
http://www.dsi.univ-paris5.fr/genatlas/fiche.php?symbol=SLC24A5 accessed – 3/2/2006
Real Tissue distribution
Real subcellular localization
Metabolic Disease:
GA-1 (Glutaric Acidemia type 1) Glutaryl CoA
Dehydrogenase (GCDH) deficiency






Lysine degradation pathway
Causes accumulation of Glutaryl CoA
~ 90% of untreated suffer acute striatal necrosis associated
with cerebral palsy for life; ~30% still have this outcome
after treatment
After age of 3, this no longer occurs
New diet-induced mouse model now allows mechanistic
studies and drug development
Key information: where is gene expressed, where do
metabolites accumulate, when, why striatum and not other
parts of brain, why age-dependent resistance?
Accessibility of information

Information accessibility despite variations in









Presentation
Purpose
Organization
Names and file formats
Relationships (ontologies)
Resolution
Quality
How up-to-date?
Solution: Semantic Web


Categorization
Computation-dependent extraction and organization of
information
Conclusions








Plan now for a wide audience
Clinician and patient involvement
User feedback will be critical to discuss and respond to
Integrate simpler models and humans
The human model will deal with critical issues that are not
possible to study in other model organisms
Functional (mutant, knock-down), developmental, and
physiological data require greater prominence
Highlight what we do NOT know for future investigation
It will be important to monitor limitations of models and
data