| Recessive dystrophic epidermolysis bullosa (RDEB) is a monogenetic blistering disease caused by loss of type VII collagen due to recessive COL7A1 gene mutations. A major complication of RDEB is squamous cell carcinomas (SCCs), with over 55% of severely affected RDEB patients dying from this cancer by age 40. The aim is to characterize protein sequences of importance in type VII collagen that may serve as potential therapeutic target in SCC. Recent studies indicate that the amino-terminal non-collagenous domain of type VII collagen (NC1) contains a 285 amino acid region (FNC1) that is required for SCC invasion in both RDEB patients and normal patients. Initial localization studies in Khavari?s laboratory suggest that the residues 760-860 of the 2,944 amino acids type VII collagen protein promote invasiveness. This project is directed at characterizing the precise type VII collagen amino acid residues that mediate neoplastic invasion. Furthermore, the hypothesis exists that type VII collagen binding to laminin-5 might comprise a protein-protein interaction critically required for epidermal tumorigenesis, and thus a major new target in SCC, therefore I will determine if invasion-promoting residues are also required for binding to laminin-5 and if these invasion-mediating sequences are dispensable for normal epidermal-dermal cohesion. |
