The development of molecular genetic approaches to the treatment of inherited metabolic and endocrine diseases will depend on the availability of animal model systems for specific diseases and on knowledge of the behavior of genes inserted into somatic cells in whole animals. Transgenic mouse technology provides potential for producing such animal models by altering the expression of special genes to create new lines of mice with metabolic or endocrine defects and evaluating the expression of specific inserted genes in every tissue throughout development. We propose to produce transgenic mice with three phenotypes: 1) Tumors of the anterior pituitary gonadotrope which may overexpress luteinizing hormone (LH) and disrupt normal development. These will serve as a model system for inherited and acquired tumor development, specifically pituitary adenomas. 2) Decreased expression of the LH beta or alpha-subunit genes, producing deficiencies of LH, as a general approach to inhibiting specific gene expression. This technology will allow development of models for endocrine and metabolic defects and methodology for the inhibition of specific gene expression in whole animals, which is ultimately relevant for corrective gene therapy. 3) Production of the placental analog of LH, chorionic gonadotropin (CG), in the gonadotrope, under the control of luteinizing hormone regulatory signals. This serves as a model for inducing targeted tissue-specific, positive gene expression which will be crucial in the development of genetic therapies. These approaches are innovative and high risk and will contribute significantly not only to the advancement of genetic therapy for inherited metabolic and endocrine disease, but also to an understanding of the role of gonadotropes and luteinizing hormone in development and reproductive physiology.
