NEW MODEL FOR HUMAN DISEASES

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.