While the cytokeratins are the most abundant proteins of epidermis and epithelia, their role in the structural and functional integration of the cell with its external environments has not been completely described. Detailed definition of cytokeratin structural interactions is a prerequisite to understanding cytoskeletal function and control in normal and diseased epithelia. In aberrant epidermal differentation, present in such disease states as psoriasis, atopic dermatitis, warts and a group of diseases classified as ichthyosis, there are cytokeratin alterations. Neoplasias of the epidermis and other epithelial tissues also show cytoskeletal changes. The biochemical heterogeneity of the non- helical portions of the cytokeratins appear to be a key feature in determining the specificity of their interactions. This structural heterogeneity will be examined by detailed epitope mapping of isolated keratins and keratin fragments with monoclonal antibodies, emphasizing sites where keratins interact with each other and with filaggrin. These interactions will be elucidated through the use of competition studies both in solution and by solid-phase immunoassay using peptides generated by proteolytic and enzymatic cleavage of keratins and by monoclonal antibody inhibition of keratin-keratin and keratin-filaggrin interactions. The effects of alterations in the physiological environment of the keratinocyte and the expression of cytokeratins also will be determined. Changes in cytokeratin interactions induced by alterations in calcium content, retinoid and cyclic nucleotide level, as well as in the presence of tumor promotors, will be examined. With this new knowledge there will be increased understanding of the potential consequences of the alteration of cytoskeleton in disease states. This will allow the development of new and safer forms of therapy for the diseases and disorders mentioned above since that therapy can be used with a better understanding of the interactions involved.