Flashcards in Chapter 6 - Animal Models and Drug Discovery Deck (30):
give three systems that model physiology
2. CNS function
give four systems that model pathology
1. genetic manipulation
2. drug induced
4. surgically induced
what must be done before a person is allowed to test on animals?
a license must be held, obtained from the home office: animals (scientific procedures) act 1986
what are the steps to getting a drug to pre-clincal trials?
1. observation - people are dying
2. basic research - gain an understanding of the cause of the disease
3. discover a target
4. find a drug that can at at this target
5. pre-clinical trials
why are animal models used?
to discern physiology as well as the cause of disease, leading to novel therapeutics
name a long-standing treatment for chronic inflammatory condition
what are the therapeutic effects of glucocorticoids
1. decreased vasodilation
2. decreased leukocyte migration/ activation
3. decreased fibrosis
4. decreased clonal expansion of B and T cells
5. decreased production of interleukins, TNF-alpha
6. decreased generation of prostaglandins
side-effects of prolonged use of glucocorticoids
1. suppresion of response to injury and infection
3. increased abdominal fat
4. skin thinning
6. increased appetite
8. moon face
9. buffalo hump
10. peptic ulceration
what effects do glucocorticoids have on mono/ poly nuclear phagocytosis
1. decreased chemotaxis
2. decreased diapedesis
3. decreased adhesion
4. decreased spreading
5. decreased endocytosis
6. decreased cytotoxicity
what effects do glucocorticoids have on T cells?
1. increased lysis (not human)
2. increased apoptosis (immature)
1. decreased proliferation
2. decreased growth differentiation
3. decreased cytotoxicity
4. decreased cytokine production
what effects do glucocorticoids have on B cells?
1. increased plasma cell formation
2. increased antibody production (low dose GC)
1. decreased antibody body production (high dose GC)
2. decreased antigen prensentation
where is TNF-alpha secreted from?
what does TNF-alpha do?
1. increases adhesion molecues on endothelial cells
2. t-cell activation
3. cytokine production (IL-6, IL-1)
4. VEGF anf angiogenesis
5. increased body temperature
what does TNF-alpha do i arthritis
activates T-cells as well as generating a cytokine cascade resulting in inflammation and bone and cartilage destruction
what was done to model rheumatoid arthritis?
an injection of an emulsion of collagen in complete Freund's adjuvant induces an immune response against collagen
the collagen induced arthritis was scored from 0-4 where
0 was no evidence of erthema and swelling
4 was erytheme and sever swelling of joints
what results were concluded from the animal model of RA in mice?
TNF-alpha was shown to ameliorate and portect collagen in CIA
human trials of infliximab (human/mouse antibodies) was highly successful
what is MS?
inflammatory demyelinating disease of the CNS
how many people does CNS affect in the UK?
what is the average MS onset age
what is the gender ratio of people with MS?
What are the standard disease modifying treatments for MS?
type 1 interferon
what was done to model MS?
experimental autoimmune encephalomyelitis (EAE)
an injection of MOG in complete Freund's adjuvant followed by an injection of pertussis toxin
severity was scored from 0-4 where
0 was normal
4 was complete hind limb paralysis
5 was moribund state / sacrifice for human reasons
what is atherosclerosis?
chronic disease of the arteries
what is the average onset of atherosclerosis in men?
>45 but begins in childhood
what is the result of coronary atherosclerosis?
partial occlusion of coronary vessels by atheromatous deposits results in:
1. angina - insufficient oxygen supply to myocardium
2. myocardial infarction - death of an area of the myocardium due to the sudden block of a thrombosis
what are knockout mice used for?
study of the role of gene function
what is apoliprotein E?
a glycoprotein synthesis mainly in the brain and liver
a constituent of all lipoproteins except LDL
synthesised by mononuclear phagocytes in blood vessels and has local effects on cholesterol homeostasis
how is a cre/loxP system made
a mouse with a gene insertion in between two loxP sites is crossed with a cre mouse
the lox p has binding sites for cre, which is a DNA recombinase so is useful for splicing and DNA recombination
the two are crossed to circumvent the embryonic lethality of changing too many genes
why is the cre/loxP system useful
it allows the examination of the role of a particular gene in a specific cell