Monte Westerfield ILAR Presentation

Monte Westerfield, University of Oregon, Eugene, USA

Sponsored by the Office of the Director National Institutes of Health,
the National Human Genome Research Institute,
the National Institute of Child Health & Development,
the National Institute of Deafness & Other Disorders
the National Eye Institute, and the Megan and Vision for a Cure Foundations
Reproducibility with zebrafish models
of human health and disease
VisionForACure.com
•Why zebrafish?
•Current use in biomedical research
•Improving reproducibility
Reproducibility with zebrafish models
of human health and disease
zebrafish
fly
human
zebrafish
Study development directly in
transparent embryos
(Karlstrom & Kane)
cell-specific promoter GFP
Tol2
Tol2 Tol2kit
Inject into zebrafish
Reporter constructs & highly
efficient transgenesis
Screen for rescue Assays: OKR, ERG, tap test, apoptosis,
etc.
Models for translational studies
Study physiology directly
(Wilkinson laboratory)
Study cellular interactions
Study blood flow directly in live animals
(Santoro laboratory)
(Keller & Ahrens, 2013)
Study activity of every neuron in the
brain simultaneously
High-throughput optical screening
(Pardo-Martin et al., 2010)
•Why zebrafish?
• in vivo analyses at high resolution
• rapid, inexpensive
•Current use in biomedical research
•Improving reproducibility
Reproducibility with zebrafish models
of human health and disease
Growth of zebrafish research
H. sapiens/130
M. musculus/20
D. melanogaster
D. rerio
C. elegans
Acute radiation syndrome
Age-related macular degeneration
Alcoholism
Alcoholic liver disease
Alzheimers disease
Anophthalmia
Anxiety disorders
Atherosclerosis
Autism
Autosomal dominant hearing disease
Axenfeld-Rieger syndrome
Bardet-Biedl syndrome
Barth syndrome
Bicuspid aortic valve disease
Biliary atresia
Cancer
Colorectal cancer
Head and neck squamous cell carcinoma
Glioma
Invasive carcinoma
LEOPARD syndrome
Leukemia
Liver cancer
Lymphoblastic leukemia
Melanoma
Myologenous leuekmia
Neuroblastoma
Pancreatic cancer
Rhabdomyosarcoma
Centronuclear myopathies
Cerebral cavernous malformations
Cholera
Chronic granulomatous disease
Chronic kidney disease
Circulatory diseases
Colitis
Congenital cataract
Congenital glycoslyation diseases
Core binding factor leukemia
Corneal dystrophies
Cranial facial diseases
Crohns disease
Cutis laxa
Cystic fibrosis
Delayed puberty
Diabetes
Diamond Blackfan anemia
Duchenne muscular dystrophy
End stage renal disease
Emphysema
Epilepsy
Extrinsic asthma
Eye diseases
Facioscapulohumeral muscular dystrophy
Fanconi anemia
Fatty liver disease
Fetal alcohol syndrome
Focal segmental glomerulosclerosis
Fraser syndrome
Ganglioside sialidase deficiency disease
GAPO progeroid syndrome
Glaucoma
Glioblastoma
Heart disease
Atrial fibrillation
Cardiac arrhythmia
Cardiac conduction diseases
Cardiomegaly
Congestive heart failure
Hypertrophic cardiomyopathy
Sudden cardiac arrest
Hepatic steatosis
Hereditary retinal degenerations
Hirschsprung disease
HIVAIDS
Holt Oram syndrome
Hyperammonemia
Hypertension
Inflammatory bowel disease
Intracranial aneurysm
J oubert syndrome
J uvenile hydrocephalus
Kidney diseases
Long QT syndrome
Lysosomal disease mucolipidosis II
Microphthamia
Midfacial cleft disease
Multiple sclerosis
Mucolipidosis type IV
Muscular dystrophy
Myotonic dystrophy
Nephronophthisis
Nonsyndromic cleft lip and palate
Noonan syndrome
Obesity
Oral cleft diseases
Osteoporosis
Parkinson disease
Polycystic kidney disease
Pseudoxanthoma elasticum
Refractory anemia
Schizophrenia
Scoliosis
Skeletal diseases
Sleep disorders
Spinal cord regeneration
Spinal muscular atrophy
Stroke
Treacher Collins syndrome
Tuberculosis
Usher syndrome
Uveal coloboma
Vascular thrombosis
von Willebrand disease
Human diseases studied with zebrafish models
(NIH funded grants, 2013)
Acute radiation syndrome
Age-related macular degeneration
Alcoholism
Alcoholic liver disease
Alzheimers disease
Anophthalmia
Anxiety disorders
Atherosclerosis
Autism
Autosomal dominant hearing disease
Axenfeld-Rieger syndrome
Bardet-Biedl syndrome
Barth syndrome
Bicuspid aortic valve disease
Biliary atresia
Cancer
Colorectal cancer
Head and neck squamous cell carcinoma
Glioma
Invasive carcinoma
LEOPARD syndrome
Leukemia
Liver cancer
Lymphoblastic leukemia
Melanoma
Myologenous leuekmia
Neuroblastoma
Pancreatic cancer
Rhabdomyosarcoma
Centronuclear myopathies
Cerebral cavernous malformations
Cholera
Chronic granulomatous disease
Chronic kidney disease
Circulatory diseases
Colitis
Congenital cataract
Congenital glycoslyation diseases
Core binding factor leukemia
Corneal dystrophies
Cranial facial diseases
Crohns disease
Cutis laxa
Cystic fibrosis
Delayed puberty
Diabetes
Diamond Blackfan anemia
Duchenne muscular dystrophy
End stage renal disease
Emphysema
Epilepsy
Extrinsic asthma
Eye diseases
Facioscapulohumeral muscular dystrophy
Fanconi anemia
Fatty liver disease
Fetal alcohol syndrome
Focal segmental glomerulosclerosis
Fraser syndrome
Ganglioside sialidase deficiency disease
GAPO progeroid syndrome
Glaucoma
Glioblastoma
Heart disease
Atrial fibrillation
Cardiac arrhythmia
Cardiac conduction diseases
Cardiomegaly
Congestive heart failure
Hypertrophic cardiomyopathy
Sudden cardiac arrest
Hepatic steatosis
Hereditary retinal degenerations
Hirschsprung disease
HIVAIDS
Holt Oram syndrome
Hyperammonemia
Hypertension
Inflammatory bowel disease
Intracranial aneurysm
J oubert syndrome
J uvenile hydrocephalus
Kidney diseases
Long QT syndrome
Lysosomal disease mucolipidosis II
Microphthamia
Midfacial cleft disease
Multiple sclerosis
Mucolipidosis type IV
Muscular dystrophy
Myotonic dystrophy
Nephronophthisis
Nonsyndromic cleft lip and palate
Noonan syndrome
Obesity
Oral cleft diseases
Osteoporosis
Parkinson disease
Polycystic kidney disease
Pseudoxanthoma elasticum
Refractory anemia
Schizophrenia
Scoliosis
Skeletal diseases
Sleep disorders
Spinal cord regeneration
Spinal muscular atrophy
Stroke
Treacher Collins syndrome
Tuberculosis
Usher syndrome
Uveal coloboma
Vascular thrombosis
von Willebrand disease
Human diseases studied with zebrafish models
(NIH funded grants, 2013)
Alzheimers Disease
Acute radiation syndrome
Age-related macular degeneration
Alcoholism
Alcoholic liver disease
Alzheimers disease
Anophthalmia
Anxiety disorders
Atherosclerosis
Autism
Autosomal dominant hearing disease
Axenfeld-Rieger syndrome
Bardet-Biedl syndrome
Barth syndrome
Bicuspid aortic valve disease
Biliary atresia
Cancer
Colorectal cancer
Head and neck squamous cell carcinoma
Glioma
Invasive carcinoma
LEOPARD syndrome
Leukemia
Liver cancer
Lymphoblastic leukemia
Melanoma
Myologenous leuekmia
Neuroblastoma
Pancreatic cancer
Rhabdomyosarcoma
Centronuclear myopathies
Cerebral cavernous malformations
Cholera
Chronic granulomatous disease
Chronic kidney disease
Circulatory diseases
Colitis
Congenital cataract
Congenital glycoslyation diseases
Core binding factor leukemia
Corneal dystrophies
Cranial facial diseases
Crohns disease
Cutis laxa
Cystic fibrosis
Delayed puberty
Diabetes
Diamond Blackfan anemia
Duchenne muscular dystrophy
End stage renal disease
Emphysema
Epilepsy
Extrinsic asthma
Eye diseases
Facioscapulohumeral muscular dystrophy
Fanconi anemia
Fatty liver disease
Fetal alcohol syndrome
Focal segmental glomerulosclerosis
Fraser syndrome
Ganglioside sialidase deficiency disease
GAPO progeroid syndrome
Glaucoma
Glioblastoma
Heart disease
Atrial fibrillation
Cardiac arrhythmia
Cardiac conduction diseases
Cardiomegaly
Congestive heart failure
Hypertrophic cardiomyopathy
Sudden cardiac arrest
Hepatic steatosis
Hereditary retinal degenerations
Hirschsprung disease
HIVAIDS
Holt Oram syndrome
Hyperammonemia
Hypertension
Inflammatory bowel disease
Intracranial aneurysm
J oubert syndrome
J uvenile hydrocephalus
Kidney diseases
Long QT syndrome
Lysosomal disease mucolipidosis II
Microphthamia
Midfacial cleft disease
Multiple sclerosis
Mucolipidosis type IV
Muscular dystrophy
Myotonic dystrophy
Nephronophthisis
Nonsyndromic cleft lip and palate
Noonan syndrome
Obesity
Oral cleft diseases
Osteoporosis
Parkinson disease
Polycystic kidney disease
Pseudoxanthoma elasticum
Refractory anemia
Schizophrenia
Scoliosis
Skeletal diseases
Sleep disorders
Spinal cord regeneration
Spinal muscular atrophy
Stroke
Treacher Collins syndrome
Tuberculosis
Usher syndrome
Uveal coloboma
Vascular thrombosis
von Willebrand disease
Human diseases studied with zebrafish models
(NIH funded grants, 2013)
Autism
Acute radiation syndrome
Age-related macular degeneration
Alcoholism
Alcoholic liver disease
Alzheimers disease
Anophthalmia
Anxiety disorders
Atherosclerosis
Autism
Autosomal dominant hearing disease
Axenfeld-Rieger syndrome
Bardet-Biedl syndrome
Barth syndrome
Bicuspid aortic valve disease
Biliary atresia
Cancer
Colorectal cancer
Head and neck squamous cell carcinoma
Glioma
Invasive carcinoma
LEOPARD syndrome
Leukemia
Liver cancer
Lymphoblastic leukemia
Melanoma
Myologenous leuekmia
Neuroblastoma
Pancreatic cancer
Rhabdomyosarcoma
Centronuclear myopathies
Cerebral cavernous malformations
Cholera
Chronic granulomatous disease
Chronic kidney disease
Circulatory diseases
Colitis
Congenital cataract
Congenital glycoslyation diseases
Core binding factor leukemia
Corneal dystrophies
Cranial facial diseases
Crohns disease
Cutis laxa
Cystic fibrosis
Delayed puberty
Diabetes
Diamond Blackfan anemia
Duchenne muscular dystrophy
End stage renal disease
Emphysema
Epilepsy
Extrinsic asthma
Eye diseases
Facioscapulohumeral muscular dystrophy
Fanconi anemia
Fatty liver disease
Fetal alcohol syndrome
Focal segmental glomerulosclerosis
Fraser syndrome
Ganglioside sialidase deficiency disease
GAPO progeroid syndrome
Glaucoma
Glioblastoma
Heart disease
Atrial fibrillation
Cardiac arrhythmia
Cardiac conduction diseases
Cardiomegaly
Congestive heart failure
Hypertrophic cardiomyopathy
Sudden cardiac arrest
Hepatic steatosis
Hereditary retinal degenerations
Hirschsprung disease
HIVAIDS
Holt Oram syndrome
Hyperammonemia
Hypertension
Inflammatory bowel disease
Intracranial aneurysm
J oubert syndrome
J uvenile hydrocephalus
Kidney diseases
Long QT syndrome
Lysosomal disease mucolipidosis II
Microphthamia
Midfacial cleft disease
Multiple sclerosis
Mucolipidosis type IV
Muscular dystrophy
Myotonic dystrophy
Nephronophthisis
Nonsyndromic cleft lip and palate
Noonan syndrome
Obesity
Oral cleft diseases
Osteoporosis
Parkinson disease
Polycystic kidney disease
Pseudoxanthoma elasticum
Refractory anemia
Schizophrenia
Scoliosis
Skeletal diseases
Sleep disorders
Spinal cord regeneration
Spinal muscular atrophy
Stroke
Treacher Collins syndrome
Tuberculosis
Usher syndrome
Uveal coloboma
Vascular thrombosis
von Willebrand disease
Human diseases studied with zebrafish models
(NIH funded grants, 2013)
Obesity
Acute radiation syndrome
Age-related macular degeneration
Alcoholism
Alcoholic liver disease
Alzheimers disease
Anophthalmia
Anxiety disorders
Atherosclerosis
Autism
Autosomal dominant hearing disease
Axenfeld-Rieger syndrome
Bardet-Biedl syndrome
Barth syndrome
Bicuspid aortic valve disease
Biliary atresia
Cancer
Colorectal cancer
Head and neck squamous cell carcinoma
Glioma
Invasive carcinoma
LEOPARD syndrome
Leukemia
Liver cancer
Lymphoblastic leukemia
Melanoma
Myologenous leuekmia
Neuroblastoma
Pancreatic cancer
Rhabdomyosarcoma
Centronuclear myopathies
Cerebral cavernous malformations
Cholera
Chronic granulomatous disease
Chronic kidney disease
Circulatory diseases
Colitis
Congenital cataract
Congenital glycoslyation diseases
Core binding factor leukemia
Corneal dystrophies
Cranial facial diseases
Crohns disease
Cutis laxa
Cystic fibrosis
Delayed puberty
Diabetes
Diamond Blackfan anemia
Duchenne muscular dystrophy
End stage renal disease
Emphysema
Epilepsy
Extrinsic asthma
Eye diseases
Facioscapulohumeral muscular dystrophy
Fanconi anemia
Fatty liver disease
Fetal alcohol syndrome
Focal segmental glomerulosclerosis
Fraser syndrome
Ganglioside sialidase deficiency disease
GAPO progeroid syndrome
Glaucoma
Glioblastoma
Heart disease
Atrial fibrillation
Cardiac arrhythmia
Cardiac conduction diseases
Cardiomegaly
Congestive heart failure
Hypertrophic cardiomyopathy
Sudden cardiac arrest
Hepatic steatosis
Hereditary retinal degenerations
Hirschsprung disease
HIVAIDS
Holt Oram syndrome
Hyperammonemia
Hypertension
Inflammatory bowel disease
Intracranial aneurysm
J oubert syndrome
J uvenile hydrocephalus
Kidney diseases
Long QT syndrome
Lysosomal disease mucolipidosis II
Microphthamia
Midfacial cleft disease
Multiple sclerosis
Mucolipidosis type IV
Muscular dystrophy
Myotonic dystrophy
Nephronophthisis
Nonsyndromic cleft lip and palate
Noonan syndrome
Obesity
Oral cleft diseases
Osteoporosis
Parkinson disease
Polycystic kidney disease
Pseudoxanthoma elasticum
Refractory anemia
Schizophrenia
Scoliosis
Skeletal diseases
Sleep disorders
Spinal cord regeneration
Spinal muscular atrophy
Stroke
Treacher Collins syndrome
Tuberculosis
Usher syndrome
Uveal coloboma
Vascular thrombosis
von Willebrand disease
Human diseases studied with zebrafish models
(NIH funded grants, 2013)
Schizophrenia
Acute radiation syndrome
Age-related macular degeneration
Alcoholism
Alcoholic liver disease
Alzheimers disease
Anophthalmia
Anxiety disorders
Atherosclerosis
Autism
Autosomal dominant hearing disease
Axenfeld-Rieger syndrome
Bardet-Biedl syndrome
Barth syndrome
Bicuspid aortic valve disease
Biliary atresia
Cancer
Colorectal cancer
Head and neck squamous cell carcinoma
Glioma
Invasive carcinoma
LEOPARD syndrome
Leukemia
Liver cancer
Lymphoblastic leukemia
Melanoma
Myologenous leuekmia
Neuroblastoma
Pancreatic cancer
Rhabdomyosarcoma
Centronuclear myopathies
Cerebral cavernous malformations
Cholera
Chronic granulomatous disease
Chronic kidney disease
Circulatory diseases
Colitis
Congenital cataract
Congenital glycoslyation diseases
Core binding factor leukemia
Corneal dystrophies
Cranial facial diseases
Crohns disease
Cutis laxa
Cystic fibrosis
Delayed puberty
Diabetes
Diamond Blackfan anemia
Duchenne muscular dystrophy
End stage renal disease
Emphysema
Epilepsy
Extrinsic asthma
Eye diseases
Facioscapulohumeral muscular dystrophy
Fanconi anemia
Fatty liver disease
Fetal alcohol syndrome
Focal segmental glomerulosclerosis
Fraser syndrome
Ganglioside sialidase deficiency disease
GAPO progeroid syndrome
Glaucoma
Glioblastoma
Heart disease
Atrial fibrillation
Cardiac arrhythmia
Cardiac conduction diseases
Cardiomegaly
Congestive heart failure
Hypertrophic cardiomyopathy
Sudden cardiac arrest
Hepatic steatosis
Hereditary retinal degenerations
Hirschsprung disease
HIVAIDS
Holt Oram syndrome
Hyperammonemia
Hypertension
Inflammatory bowel disease
Intracranial aneurysm
J oubert syndrome
J uvenile hydrocephalus
Kidney diseases
Long QT syndrome
Lysosomal disease mucolipidosis II
Microphthamia
Midfacial cleft disease
Multiple sclerosis
Mucolipidosis type IV
Muscular dystrophy
Myotonic dystrophy
Nephronophthisis
Nonsyndromic cleft lip and palate
Noonan syndrome
Obesity
Oral cleft diseases
Osteoporosis
Parkinson disease
Polycystic kidney disease
Pseudoxanthoma elasticum
Refractory anemia
Schizophrenia
Scoliosis
Skeletal diseases
Sleep disorders
Spinal cord regeneration
Spinal muscular atrophy
Stroke
Treacher Collins syndrome
Tuberculosis
Usher syndrome
Uveal coloboma
Vascular thrombosis
von Willebrand disease
Human diseases studied with zebrafish models
(NIH funded grants, 2013)
Sleep disorders
•Why zebrafish?
• in vivo analyses at high resolution
• rapid, inexpensive
•Current use in biomedical research
• widespread and growing
•Improving reproducibility
Reproducibility with zebrafish models
of human health and disease
Forward genetics: thousands of mutants
Reverse genetics: morpholinos
knockdown gene function
Translation
blocker
Splice
blocker
mRNA
Problems for reproducibility:
•toxicity
•effectiveness diluted over time
•genomic polymorphisms
•off-target effects
Translation
blocker
Splice
blocker
mRNA
Reverse genetics: morpholinos
knockdown gene function
Knock out of all protein coding genes
CRISPRs provide precise genome editing
(Ebermann et al.)
Zebrafish models of human patients
(Ebermann et al.)
Potential genetic interaction between PDZD7 & USH2A
(Ebermann et al.)
Zebrafish model validates genetic
interaction between PDZD7 & USH2A
New tools increase reproducibility
•complete maps of all SNPs
•rapid, low cost sequencing
•isogenic strains
•Why zebrafish?
• in vivo analyses at high resolution
• rapid, inexpensive
•Current use in biomedical research
• widespread
•Improving reproducibility
• precise models of human patients
• improved tools needed
Reproducibility with zebrafish models
of human health and disease
Monte Westerfield, University of Oregon, Eugene, USA
Sponsored by the Office of the Director National Institutes of Health,
the National Human Genome Research Institute,
the National Institute of Child Health & Development,
the National Institute of Deafness & Other Disorders
the National Eye Institute, and the Megan and Vision for a Cure Foundations
Reproducibility with zebrafish models
of human health and disease
VisionForACure.com

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