NEW MODEL FOR HUMAN DISEASES

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This research program will lead to the establishment of the laboratory opossum (Monodelphis domestica) as a unique and appropriate mammal model for research on a variety of human diseases of importance to public health. We propose to initiate six interactive investigations that will form the basis for future large scale studies on susceptibility to human diseases (broadly classified as cancer and cardiovascular disease) and on their initiation, progression, and treatment. Furthermore, we expect that during the proposed period of this program, pilot studies using Monodelphis as a model for investigating human infectious disease and human fetal development will advance to the level of major research initiatives. The use of Monodelphis as an experimental mammal model facilitates the detection of genetic effects and interactions involved in specific diseases that may be difficult to identify in affect humans. The results of these investigations can lead to new hypotheses that can be tested with human subjects. Conversely, Monodelphis has a great deal of potential for testing hypotheses that arise from research on these diseases in humans, but can be tested only on a animal model. Project 1 will enhance the incidence, determine the progression, and generate data for genetic analysis of susceptibility to malignant melanoma, initiated at the suckling stage in Monodelphis by exposure to ultraviolet radiation alone. Project 2 will test the hypothesis that angiogenesis is a prerequisite for ultraviolet radiation-inducted mesenchymal neoplasia, using the corneal stroma in Monodelphis as a model system. Project 3 will determine the effectiveness of specific chemotherapeutic strategies, applicable to humans, for treatment of malignant melanoma and mesenchymal (corneal) neoplasia of Monodelphis, using in vitro and in vivo systems. Project 4 will examine the effects of diet and genotype on lipoprotein phenotypes and the initiation and progression of atherosclerosis in the Mondelphis model. Project 5 will be determine the genetic basis of serum cholesterol response to a high-cholesterol, saturated fat diet in Monodelphis, with the long-term goal, together with Project 4, of identifying specific genes that control dietary responsiveness. Project 6 will establish a basic linkage map of the Monodelphis genome and will use this map to identify associations between specific alleles and the phenotypes of interest in the other projects. The six Projects are supported by a Core Unit for animal resource management, data management and analysis, various research services, and administration.