Biomedical animal models

Pradeep Patil

Why animals used in research?
• • • • • Organ and body similar Suceptibility to same diseases Short life span Controlled environment/less variables Rodent 90% + other 10%

When to be used? • Literature research/comparison with previous data • Computer models or cell culture • IACUC approval • Extensive training. education and care/mgt • But before human clinical trial .

negotiation between doctor and patient. or defect.society • are very much dependent on a person's actions and beliefs. pain. • Focus pathology. • Limiting . thus making the normal human condition "healthy".biomedical model definition • Health .freedom from disease. the biochemistry and the physiology. • Neglects . • heart disease • type 2diabetes mellitus .

Classification 1. Orphan models . Negative models 5. Induced (experimental) models 2. Genetically modified models 4. mutant) models 3. Spontaneous (genetic.

Limitation FIV\HIV in cats vs simian vs mouse model schistosomiasis (mansoni) in mice vs rats .INDUCED (EXPERIMENTAL) MODELS Models – induction of diabetes mellitus with encephalomyocarditis virus – allergy against cow’s milk through immunization with minute doses of protein – partial hepatectomy to study liver regeneration.

Other induced models eg • • • • • • • • • • • • The use of metrazol (pentylenetetrazol) as an animal model of epilepsy[6] Immunisation with an auto-antigen to induce an immune response to model autoimmune diseases such as Experimental autoimmune encephalomyelitis[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 with agonists or antagonists of various neurotransmitters to reproduce human mental disorders Using ionizing radiation to cause tumors Implanting 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 .

SPONTANEOUS ANIMAL MODELS • Naturally occurring genetic variants (mutants). – type I diabetes in humans and insulin requiring diabetes in the BB rat. – athymic nude mouse – Snell’s Dwarf mouse without a functional pituitary – curly tail mouse in which fetuses develop a whole range of neural tube defects. .

.GENETICALLY MODIFIED MODELS • Rapid developments in genetic engineering and embryo manipulation technology during the past decade have made lots of transgenic disease models.

NEGATIVE MODELS • Negative model is the term used for species. or breeds in which a certain disease does not develop. e.g.. . gonococcal infection in rabbits • Their main application is studies on the mechanism of resistance to gain insight into its physiological basis. strains.

. Visna virus feline leukemia virus. and which is recognized when a similar human disease is later identified. – – – – – Marek’s disease Papillomatosis BSE.ORPHAN MODELS • A functional disorder that occurs naturally in a nonhuman species but has not yet been described in humans.

. – acute as 8–28 days – subacute as 4–12 weeks Acute liver failure (ALF) (also called fulminant hepatic failure) is a relatively rare condition .Acute liver failure model • loss of function of 80-90% of liver cells – hyperacute as within 1 week.

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under isoflurane anesthesia. .Models • The monkeys are treated using liver-directed radiation therapy. 24-30 kg. followed by mild hepatoxic injury to induce acute liver failure symptoms that are strikingly similar to those in humans.5 g/kg Dgalactosamine intravenously. • male hounds. were administered 1. • Retrorsine/CCl4 – induced acute liver failure rat model.

Models Anhepatic models Hepatic devascularization Total hepatectomy Toxin models Portocaval shunt. hepatic artery ligation One of two stage procedure Dose dependent hepatotoxins Biotransformed hepatotoxins Viral models Galactosamine Thioacetamide Acetaminophen Murine hepatitis virus .

ALF • Lethal --BAL – Anhepatic – Vascular occlusion • Non lethal ==cell transplantation – Toxins – Toxins + PH .

• Pale with focal coagulative necrosis . DNA and protein in normal and cancer cell.Dgal toxicity • synthesis of UDP-sugar derivatives from D gal • Depletion of uracil group • Inhibitory effect on biosynthesis of RNA.

• The liver glycogen store was almost completely exhausted. • Forty-eight hours after the first injection the histologic picture was much more severe than after 1 day . closely related to those found in acute human viral hepatitis.• morphologic and functional features. were observed after intraperitoneal administration of galactosamine.

i. a pyrrolizidine alkaloid is hepatotoxic and carcinogenic.p.) was administered as a soluition in 0-9% NaCl. – Or 2 injections of 30 mg/kg each. – (40mg.Retrorsine • Retrorsine. . 2 weeks apart • centrilobular necrosis and haemorrhage. body wt../kg.

.MOA • PAS are known for their ability to inhibit hepatocyte cell division (3-7). after administration. total liver protein was lower than the control value 15 hr. after treatment with the alkaloid. suggesting impairment of hepatic protein synthesis. and such inhibition can last for several weeks following a single exposure • induced nuclear changes and a decrease in liver RNA concentration 30min.

7mg/gm Dgal .Models • Pigs – ischemia of liver for 6 to 10 hr • Mouse Model of Liver Disease – humasnised liver • 0.

AFP. transferrin.After animal sample retrieval • Tissue – Buffer formalin – Frozen • Serum Techniques • HE • IHC (frozen). HNFa/b. EBPa/b. P53. 19. bTubulin. a fetoprotein • ELIZA – ALBUMIN • WB– UGT1a1.albumin • IHC (paraffin)– CK8. Hep Ag. . CYP3A1/4.

• The completion of the map of the mouse genome and the dominating position of mice in transgenic research seem to indicate that the dominance of the mouse as the most popular model for humans will increase even more in the future.Conclusion • The selection of an animal model depends on a number of factors relating to the hypothesis to be tested. . but often more practical aspects associated with the project and with project staff and experimental facilities play a significant role.

References .