Disease model

Immunosuppression induced by sirolimus (36) appears to be mediated by a mechanism distincdy different from that of either cyclosporin or FK-506. Sirolimus markedly suppresses IL-2 or IL-4-driven T-ceU proliferation. The preclinical studies suggest that sirolimus is a potent immunosuppressive agent in transplantation and autoimmune disease models. The clinical potential of this agent depends on its toxicity profile (80). 

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A protease-specific model has also been reported in which a replication-defective adenovirus encoding an NS3 protease-SEAP fusion protein is injected into mouse tail veins, resulting in expression of the fusion protein in the liver [82, 83]. Protease activity can be detected both by measuring activity of liberated SEAP or by protease-induced liver damage. Protease activity was found to be reduced by administration of protease inhibitors. This model can be used to show that candidate inhibitors have adequate pharmacokinetic properties in mice to function in the intended target organ, but it is not a true disease model. 

Fig. 4. Regulation by chemokines of recruited DC-mediated immune responses, (a) The effect of CCL21 on mDC migration in liver disease model, (b) The effect of CXCL9 on pDC migration in skin infection model.

Rosario MC, Jacqmin P, Dorr P, van der Ryst E, Hitchcock C. A pharmacokinetic-pharmacodynamic disease model to predict in vivo antiviral activity of maraviroc. Clin Pharmacol Ther 2005 78(5) 508-519. 

The last step of the drug discovery process involves the testing of lead compounds to address issues such as efficacy, bioavailability, and safety. Testing may include in vitro assays but ultimately would require a suitable disease model and studies in animals. Many compounds may need to be designed and synthesized to identify the one compound with all the desired properties. Such a compound can be advanced to preclinical studies and eventually to the clinic. 

Human prion disease models have also been developed in mice [154,155]. Crossing the species barrier into an experimentally accessible animal system, the prions responsible for Creutzfeldt Jakob disease, new variant CJD, Gerstmann-Straussler-Scheinker disease, and fatal familial insomnia produce a reproducible time-dependent neuronal degeneration leading to death. 

Kim, S.R., Jang, Y.P., Jockusch, S., Fishkin, N.E., Turro, N.J., Sparrow, J.R., 2007b. The all-trans-retinal dimer series of lipofuscin pigments in retinal pigment epithelial cells in a recessive Stargardt disease model. Pmc Natl Acad Sci USA. 104, 19273-19278. 

Medhurst AD et al. The use of TaqMan RT-PCR assays for semiquantitative analysis of gene expression in CN S tissues and disease models. J Neurosci Methods 2000 98 9-20. 

Shiffman D et al. Gene expression profiling of cardiovascular disease models. Curr Opin Biotechnol 2000 11 598-601. 

Joseph J, Arendash G, Gordon M, Diamond D, Shukitt-Hale B and Morgan D. 2003. Blueberry supplementation enhances signaling and prevents behavioral deficits in an Alzheimer disease model. Nutr Neurosci 6 153-163. 

Hopwood, J. J., Crawley, A. C. and Taylor, R. M. Spontaneous and engineered mammalian storage disease models. In F. M. Platt and S. U. Walkley (eds), Lysosomal Disorders of the Brain. New York Oxford University Press, 2004, pp. 257-289. 

Dodart, J. C., Bales, K. R., Gannon, K. S. et al. Immunization reverses memory deficits without reducing brain A(3 burden in Alzheimer s disease model. Nature Neurosci. 5 452M57, 2002. 

De Haar, C., et al., Ultrafine carbon black particles cause early airway inflammation and have adjuvant activity in a mouse allergic airway disease model, Toxicol. Sci. 87, 2, 409, 2005. 

Fairweather, D. and Rose, N.R., Models of coxsackievirus B3-induced myocarditis Recent advances, Drug Discovery Today Disease Models, 1,381, 2004. 

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