Transgenic TGF-Alpha or EGFR1 Overexpression Mouse Model for Symptom Complex Research

摘要

Running wheel studies were conducted on two strains of transgenic mice to test the hypothesis that ligands of the EGFR inhibit hypothalamic modulatory centers regulating 24 hour rest/activity and other circadian functions. Running wheel activity (RWA) was used first to assess the structure (PERIOD) of the rest and activity phases in 12 hour lights on and off (LD) and in constant darkness (DD) conditions. Period was found to be approximately 24 hours in LD and DD conditions for both the transgenic TGF-alpha and EGFR overexpression mice and similar to the control animals. From this we concluded that the supra chiasmatic nucleus (SCN, master clock) in not disrupted in these animals. The second set of measurements focused on the fractional time active for the mice over 24 hours (ALPHA). These data showed that TGF-alpha overexpression animals, and not the EGFR animals, had significantly lower ALPHA. These data are consistent with a model of the EGFR ligands can produce disruption of neural signaling downstream from the SCN . We have interpreted this as a cause for fatigue associated with the overexpression of TGF-alpha as could be found in cancer patients with a tumor that produces this ligand. Next, TGF-alpha mice were treated with an EGFR tyrosine kinase inhibitor (AG1478), given by the subcutaneous route, to detect an effect in ALPHA. We could find no evidence for such an effect in this model system. Nevertheless, symptoms in cancer patients might be related to the production of neurally active cytokines and growth receptor ligands of the epidermal growth factor family. This suggests that clinical studies should examine for not only changes in tumor growth per se, but for improvement in quality of life and specific symptoms of fatigue in patients receiving anti-EGFR agents.