7/30/2019 Biomedical Animal Models 110419

1/24

Biomedical animal models

Pradeep Patil

7/30/2019 Biomedical Animal Models 110419

2/24

7/30/2019 Biomedical Animal Models 110419

3/24

When to be used?

Literature research/comparison with previousdata

Computer models or cell culture IACUC approval Extensive training, education and care/mgt

But before human clinical trial

7/30/2019 Biomedical Animal Models 110419

4/24

biomedical model definition Health - freedom from disease, pain, or defect, thus

making the normal human condition "healthy".

Focus pathology , the biochemistry and the physiology .

Neglects - negotiation between doctor and patient.

Limiting - society are very much dependent on a person's actions and beliefs.

heart disease type 2 diabetes mellitus

http://en.wikipedia.org/wiki/Pathologyhttp://en.wikipedia.org/wiki/Biochemistryhttp://en.wikipedia.org/wiki/Physiologyhttp://en.wikipedia.org/wiki/Societyhttp://en.wikipedia.org/wiki/Diabetes_mellitushttp://en.wikipedia.org/wiki/Diabetes_mellitushttp://en.wikipedia.org/wiki/Societyhttp://en.wikipedia.org/wiki/Physiologyhttp://en.wikipedia.org/wiki/Biochemistryhttp://en.wikipedia.org/wiki/Pathology

7/30/2019 Biomedical Animal Models 110419

5/24

Classification

1. Induced (experimental) models2. Spontaneous (genetic, mutant) models

3. Genetically modified models4. Negative models5. Orphan models

7/30/2019 Biomedical Animal Models 110419

6/24

INDUCED (EXPERIMENTAL) MODELS

Models induction of diabetes mellitus with

encephalomyocarditis virus allergy against cows milk through immunization

with minute doses of protein partial hepatectomy to study liver regeneration.

LimitationFIV\HIV in cats vs simian vs mouse model

schistosomiasis (mansoni) in mice vs rats

7/30/2019 Biomedical Animal Models 110419

7/24

Other induced models eg The use of metrazol (pentylenetetrazol) as an animal model of epilepsy [6] Immun isation with an auto- antigen to induce an immune respon se to

model autoimmun e diseases such as Experimental autoimmuneencephalomyelitis [7]

Occlusion of the middle cerebral artery as an animal model of ischemic stroke [8] Injection of blood in the basal ganglia of mice as a model for stroke [9] Infecting animals with pathogens to reproduce human infectious diseases Injecting animals w ith agonists or antagonists of various neurotransmitters to

reproduce human mental disorders Using ionizing radiation to cause tumors Implantin g animals with tumors to test and develop treatments using ionizing

radiation Genetically selected (such as in diabetic mice also known as NOD mice )[10] Various animal models for screening of drugs for the treatment of glaucoma The use of the ovariectomized rat in osteoporosis research Use of Plasmodium yoelii as a model of human malaria [11][12][13

http://en.wikipedia.org/wiki/Metrazolhttp://en.wikipedia.org/wiki/Epilepsyhttp://en.wikipedia.org/wiki/Animal_modelhttp://en.wikipedia.org/wiki/Immunisationhttp://en.wikipedia.org/wiki/Autoimmune_diseaseshttp://en.wikipedia.org/wiki/Autoimmune_diseaseshttp://en.wikipedia.org/wiki/Autoimmune_diseaseshttp://en.wikipedia.org/wiki/Antigenhttp://en.wikipedia.org/wiki/Experimental_autoimmune_encephalomyelitishttp://en.wikipedia.org/wiki/Experimental_autoimmune_encephalomyelitishttp://en.wikipedia.org/wiki/Immune_responsehttp://en.wikipedia.org/wiki/Experimental_autoimmune_encephalomyelitishttp://en.wikipedia.org/wiki/Experimental_autoimmune_encephalomyelitishttp://en.wikipedia.org/wiki/Animal_modelhttp://en.wikipedia.org/wiki/Autoimmune_diseaseshttp://en.wikipedia.org/wiki/Experimental_autoimmune_encephalomyelitishttp://en.wikipedia.org/wiki/Experimental_autoimmune_encephalomyelitishttp://en.wikipedia.org/wiki/Animal_modelhttp://en.wikipedia.org/wiki/Middle_cerebral_arteryhttp://en.wikipedia.org/wiki/Animal_models_of_ischemic_strokehttp://en.wikipedia.org/wiki/Animal_modelhttp://en.wikipedia.org/wiki/Basal_gangliahttp://en.wikipedia.org/wiki/Mus_musculushttp://en.wikipedia.org/wiki/Strokehttp://en.wikipedia.org/wiki/Animal_modelhttp://en.wikipedia.org/wiki/Pathogenshttp://en.wikipedia.org/wiki/Infectious_diseaseshttp://en.wikipedia.org/wiki/Mental_disorderhttp://en.wikipedia.org/wiki/Mental_disorderhttp://en.wikipedia.org/wiki/Mental_disorderhttp://en.wikipedia.org/wiki/Mental_disorderhttp://en.wikipedia.org/wiki/Receptor_antagonisthttp://en.wikipedia.org/wiki/Neurotransmitterhttp://en.wikipedia.org/wiki/Mental_disorderhttp://en.wikipedia.org/wiki/Ionizing_radiationhttp://en.wikipedia.org/wiki/Tumorshttp://en.wikipedia.org/wiki/Ionizing_radiationhttp://en.wikipedia.org/wiki/Tumorhttp://en.wikipedia.org/wiki/Ionizing_radiationhttp://en.wikipedia.org/wiki/Ionizing_radiationhttp://en.wikipedia.org/wiki/Artificial_selectionhttp://en.wikipedia.org/wiki/Diabeteshttp://en.wikipedia.org/wiki/Mus_musculushttp://en.wikipedia.org/wiki/NOD_micehttp://en.wikipedia.org/wiki/Animal_modelhttp://en.wiktionary.org/wiki/screeninghttp://en.wikipedia.org/wiki/Glaucomahttp://en.wikipedia.org/wiki/Ovariectomized_rathttp://en.wikipedia.org/wiki/Osteoporosishttp://en.wikipedia.org/wiki/Plasmodium_yoeliihttp://en.wikipedia.org/wiki/Animal_modelhttp://en.wikipedia.org/wiki/Animal_modelhttp://en.wikipedia.org/wiki/Animal_modelhttp://en.wikipedia.org/wiki/Plasmodium_yoeliihttp://en.wikipedia.org/wiki/Plasmodium_yoeliihttp://en.wikipedia.org/wiki/Osteoporosishttp://en.wikipedia.org/wiki/Ovariectomized_rathttp://en.wikipedia.org/wiki/Ovariectomized_rathttp://en.wikipedia.org/wiki/Ovariectomized_rathttp://en.wikipedia.org/wiki/Glaucomahttp://en.wiktionary.org/wiki/screeninghttp://en.wikipedia.org/wiki/Animal_modelhttp://en.wikipedia.org/wiki/NOD_micehttp://en.wikipedia.org/wiki/Mus_musculushttp://en.wikipedia.org/wiki/Diabeteshttp://en.wikipedia.org/wiki/Artificial_selectionhttp://en.wikipedia.org/wiki/Ionizing_radiationhttp://en.wikipedia.org/wiki/Ionizing_radiationhttp://en.wikipedia.org/wiki/Tumorhttp://en.wikipedia.org/wiki/Tumorshttp://en.wikipedia.org/wiki/Ionizing_radiationhttp://en.wikipedia.org/wiki/Mental_disorderhttp://en.wikipedia.org/wiki/Neurotransmitterhttp://en.wikipedia.org/wiki/Receptor_antagonisthttp://en.wikipedia.org/wiki/Agonistshttp://en.wikipedia.org/wiki/Infectious_diseaseshttp://en.wikipedia.org/wiki/Pathogenshttp://en.wikipedia.org/wiki/Animal_modelhttp://en.wikipedia.org/wiki/Strokehttp://en.wikipedia.org/wiki/Mus_musculushttp://en.wikipedia.org/wiki/Basal_gangliahttp://en.wikipedia.org/wiki/Animal_modelhttp://en.wikipedia.org/wiki/Animal_models_of_ischemic_strokehttp://en.wikipedia.org/wiki/Middle_cerebral_arteryhttp://en.wikipedia.org/wiki/Animal_modelhttp://en.wikipedia.org/wiki/Experimental_autoimmune_encephalomyelitishttp://en.wikipedia.org/wiki/Experimental_autoimmune_encephalomyelitishttp://en.wikipedia.org/wiki/Autoimmune_diseaseshttp://en.wikipedia.org/wiki/Immune_responsehttp://en.wikipedia.org/wiki/Antigenhttp://en.wikipedia.org/wiki/Immunisationhttp://en.wikipedia.org/wiki/Animal_modelhttp://en.wikipedia.org/wiki/Epilepsyhttp://en.wikipedia.org/wiki/Metrazol

7/30/2019 Biomedical Animal Models 110419

8/24

SPONTANEOUS ANIMAL MODELS

Naturally occurring genetic variants (mutants). athymic nude mouse Snells Dwarf mouse without a functional pituitary curly tail mouse in which fetuses develop a whole

range of neural tube defects. type I diabetes in humans and insulin requiring

diabetes in the BB rat.

7/30/2019 Biomedical Animal Models 110419

9/24

GENETICALLY MODIFIED MODELS

Rapid developments in genetic engineeringand embryo manipulation technology duringthe past decade have made lots of transgenicdisease models.

7/30/2019 Biomedical Animal Models 110419

10/24

NEGATIVE MODELS

Negative model is the term used for species,strains, or breeds in which a certain diseasedoes not develop, e.g., gonococcal infection inrabbits

Their main application is studies on themechanism of resistance to gain insight intoits physiological basis.

7/30/2019 Biomedical Animal Models 110419

11/24

ORPHAN MODELS

A functional disorder that occurs naturally in anonhuman species but has not yet beendescribed in humans, and which is recognized

when a similar human disease is later identified. Mareks disease Papillomatosis

BSE, Visna virus feline leukemia virus.

7/30/2019 Biomedical Animal Models 110419

12/24

7/30/2019 Biomedical Animal Models 110419

13/24

7/30/2019 Biomedical Animal Models 110419

14/24

Models

The monkeys are treated using liver-directedradiation therapy, followed by mild hepatoxicinjury to induce acute liver failure symptoms

that are strikingly similar to those in humans. male hounds, 24-30 kg, under isoflurane

anesthesia, were administered 1.5 g/kg D-galactosamine intravenously.

Retrorsine/CCl4 induced acute liver failurerat model.

7/30/2019 Biomedical Animal Models 110419

15/24

Models

Anhepatic models

Hepatic devascularization Portocaval shunt,hepatic artery ligation

Total hepatectomy One of two stage procedure

Toxin models

Dose dependent hepatotoxins Galactosamine

Biotransformed hepatotoxins ThioacetamideAcetaminophen

Viral models Murine hepatitis virus

7/30/2019 Biomedical Animal Models 110419

16/24

ALF

Lethal --BAL Anhepatic Vascular occlusion

Non lethal ==cell transplantation Toxins Toxins + PH

7/30/2019 Biomedical Animal Models 110419

17/24

Dgal toxicity

synthesis of UDP-sugar derivatives from D gal Depletion of uracil group

Inhibitory effect on biosynthesis of RNA, DNAand protein in normal and cancer cell. Pale with focal coagulative necrosis

7/30/2019 Biomedical Animal Models 110419

18/24

morphologic and functional features, closelyrelated to those found in acute human viralhepatitis, were observed after intraperitoneal

administration of galactosamine. The liver glycogen store was almost completely

exhausted,

Forty-eight hours after the first injection thehistologic picture was much more severe thanafter 1 day

7/30/2019 Biomedical Animal Models 110419

19/24

Retrorsine

Retrorsine, a pyrrolizidine alkaloid ishepatotoxic and carcinogenic.

(40mg./kg. body wt.) was administered as asoluition in 0-9% NaCl.

Or 2 injections of 30 mg/kg each, i.p., 2 weeksapart

centrilobular necrosis and haemorrhage.

7/30/2019 Biomedical Animal Models 110419

20/24

MOA PAS are known for their ability to inhibit

hepatocyte cell division (3-7), and such inhibitioncan last for several weeks following a single

exposure induced nuclear changes and a decrease in liver

RNA concentration 30min. after administration;total liver protein was lower than the control

value 15 hr. after treatment with the alkaloid,suggesting impairment of hepatic proteinsynthesis.

7/30/2019 Biomedical Animal Models 110419

21/24

Models Pigs ischemia of liver for 6 to 10 hr Mouse Model of Liver Disease humasnised liver

0,7mg/gm Dgal

http://drugdiscoveryopinion.com/2010/02/mouse-model-of-liver-disease/http://drugdiscoveryopinion.com/2010/02/mouse-model-of-liver-disease/

7/30/2019 Biomedical Animal Models 110419

22/24

After animal sample retrieval Tissue

Buffer formalin Frozen

Serum

Techniques HE IHC (frozen)- albumin IHC (paraffin) CK8, 19, P53, Hep Ag, AFP, a fetoprotein ELIZA ALBUMIN WB UGT1a1, EBPa/b, bTubulin, transferrin, CYP3A1/4,

HNFa/b.

7/30/2019 Biomedical Animal Models 110419

23/24

Conclusion The selection of an animal model depends on a

number of factors relating to the hypothesis to betested, but often more practical aspectsassociated with the project and with project staff and experimental facilities play a significant role.

The completion of the map of the mouse genomeand the dominating position of mice in transgenicresearch seem to indicate that the dominance of the mouse as the most popular model forhumans will increase even more in the future.

7/30/2019 Biomedical Animal Models 110419

24/24