Knockout mice studies

Crucial data regarding the physiological relevance of MDR transporters came from knockout mice studies. Surprisingly, loss of these genes does not result in an obvious phenotype MDR knockout mice are viable and... 

P-gp-mediated transport. These authors underlined their results with P-gp knockout mice studies. Co-administration of digoxin and quinidine to wild-type mice resulted in a 73% increase in digoxin concentrations, whereas the increase for the knockout mice was only 20%. 

Also, research has recently indicated that TNF-a is involved in the cytotoxicity, and knockout mice studies have shown that absence of the two TNF-a receptors completely removes sensitivity to MPTP. 

Wu H, Jin Y, Buddhala C, Osterhaus G, Cohen E, Jin H, Wei J, Davis K, Obata K, Wu JY (2007) Role of glutamate decarboxylase (GAD) isoform, GAD65, in GABA synthesis and transport into synaptic vesicles-Evidence from GAD65-knockout mice studies. Brain Res 1154 80-83. 

The results of knockout mouse studies indicate that caspase function can be divided into two broad phenotypic classes, those that have primary crucial effect on animal development (proapoptotic caspases, i.e., caspase-3, -7, -8, and -9) and those that mediate immune system functions (proinflammatory caspases, i.e., caspase-1 and -11) [64, 73]. 

Sugai M, Gonda H, Nambu Y, Yokota Y, Shimizu A. Role of Id proteins in B lymphocyte activation new insights from knockout mouse studies. J Mol Med 2004 82 592-599. 

A key requirement of QSAR is that the compounds used in the modeling and prediction processes should have the same mechanism of action, and for this reason most QSAR studies are made with congeneric series of compounds. However, if a diverse set of compounds can reasonably be assumed to have the same mechanism of action, QSAR modeling can justihably be carried out. For example, Dearden et al. [43] developed a QSAR for the ratio of brain levels of 22 very diverse drugs in the wild-type mouse and the P-glycoprotein knockout mouse (R+/ ) ... 

In finalizing this series of studies, the double receptor knockout mouse (OX,k / ()X2k ) was shown to be phenotypically indistinguishable from orexin mice (Kisanuki et al, 2001), a result that makes the existence of additional orexin receptors unlikely. 

Figure 11.3 Studies in mutant mice, (a) Image of mineral to matrix in the growth plate of a young mouse lacking matrix gla protein (MGP—/—) and its wildtype control (MGP+/+). Note the gradient of mineral matrix ratios in the wildtype is not apparent in the knockout, (b) Mineral matrix increases at three sites in the cortices of the osteocalcin knockout (KO) mouse (6 month data), while crystallinity is decreased relative to wildtype (WT) controls, (c) In the osteonectin knockout mouse (4 months old) the collagen maturity assessed in terms of the 1660 1690 peak area ratio is increased on the periosteal and endosteal surface.

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