TSC is a genetic disorder in which tumor-like growths develop in multiple organ systems. Mutations of the TSC1 or TSC2 gene can cause the disease. How these mutations cause the disease is not clear. The proteins encoded by these two TSC genes bind together and inhibit the functions of a GTP-binding protein called Rheb by converting the GTP-bound Rheb into the GDP-bound form. The disease-causing mutations in TSC genes cause an increase in the active form of Rheb (GTP-bound) and thus trigger a signaling cascade that leads the cells to turn on or off genes and produce proteins. Although Rheb has been shown to be a direct target of TSC gene products, the significance of Rheb in the development of pathological lesions seen in TSC patients is not clear. Therefore, we propose to create conditional Rheb transgenic mice to examine the significance of Rheb in the development of TSC pathologies.

The strategy is to knock in Rheb gene into a particular site of a mouse chromosome, so that Rheb protein can be made in selective tissues for us to study the contribution of Rheb to the development of pathological lesions in that particular tissue, for example, brain. Although our focus is on creating a model that recapitulates the neuronal abnormalities, the Rheb transgenic mice will be useful in studying the pathological lesions in other systems as well. If the Rheb transgenic mice reproduce the abnormalities seen in TSC patients, Rheb could be a target for developing therapeutic interventions.