GENERATION OF ANIMAL MODELS AND DEFINITION OF THE MOLECULAR MECHANISMS OF THE HUMAN AMYLOID CORNEAL DYSTROPHY

The TROP1/M4S1/TACSTD1 and TROP2/M1S1/TACSTD2 are homologous genes that encode cell membrane proteins that regulate cell-cell adhesion. Trop-1 is expressed early in development and by proliferating cells, whereas Trop-2 is expressed by differentiated, non-proliferating cells. Remarkably, Trop-1 positively regulates the rate of cell growth, whereas the expression of Trop-2 dramatically reduces it. Both molecules regulate the ‘suicide’ rate of expressing cells. Recently, mutations of the human TROP2/TACSTD2 gene have been demonstrated to cause the human amyloid corneal dystrophy. Very little is known on the pathogenesis and molecular mechanisms of this genetic disease, and it is not known if an altered processing or transport of the mutated Trop causes the accumulation of amyloid material in the affected cells. Molecular diagnostic tests of human amyloid corneal dystrophy are being developed. However, no cures for this orphan disease are available. Insufficient knowledge on the mechanisms of appearance of this disease prevents the development of effective therapies. The goal of this project is to generate an animal model of amyloid corneal dystrophy where to study the molecular mechanisms of this disease. We have isolated the murine Trop1 and Trop2 genes, and these will be used for recombination and inactivation of the normal genes present in the mouse. The effective removal of the Trop genes from the mouse genome will allow to define their role in the development of the embryo and in the after-birth maintenance of epithelial tissues. The definition of potentially disrupted signal transduction pathways or of protein processing/transport defects in cells devoid of Trop will be important to understand the role of these molecules in the amyloid corneal dystrophy disease. The mice without Trop genes will also serve to test drugs for the cure of this disease and for gene therapy.