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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, Tokyo Cantonese, China Han Chinese, Beijing East Asian Total Zapotec, Mexico Indigenous American Total Yoruba, Ibadan, 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