Doug Hanahan, Ph.D.

We are genetically manipulating the mouse genome to model two complex diseases: cancer and autoimmunity. Transgenic mouse models represent perturbations that are providing insight into mechanism both of disease and of normal development.

Tumor development is being studied in several cell types, including the pancreatic islets, and the dermis and epidermis of the skin. In each case oncogenes have been introduced into transgenic mice to endow the heritable development of tissue-specific tumors. There are notable similarities in these tumor development pathways, suggestive of common principles. Current areas of investigation include: the multiple signals needed to induce malignant proliferation; the possibility that programmed cell death attempts to counteract such inappropriate proliferation; the positive and negative regulators of tumor angiogenesis, the growth of new blood vessels; and screens for new genes involved in these tumorigenesis pathways.

Immune self-tolerance and its relationship to autoimmunity is being modeled by expression of a novel antigen, SV40 Tag, in the pancreatic beta cells, which are destroyed by the immune system in type I diabetes. Families of transgenic mice show two alternative phenotypes: self tolerance of Tag, or autoimmunity. The tolerant mice express Tag in beta cells and thymus during development, in contrast to the autoimmune mice, who first express Tag as adults. We are characterizing cellular mechanisms and sites of tolerance induction, and the parameters of autoimmunity. Current approaches include organ transplants of thymus and pancreas, and the use of transgenic mice carrying a rearranged T cell receptor reactive to Tag, which allows Tag-specific T-lymphocytes to be monitored in both tolerant and autoimmune genetic backgrounds.