REGULATION OF DIFFERENTIATION IN HUMAN EPITHELIAL CELLS

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DESCRIPTION: (Adapted from the applicant's abstract) This is a re-submission of an application originally for a project grant but now changed to one for a FIRST Award. The investigator suggests that inductive interactions are critical to normal development in vertebrate embryos. The interactions may include the presence of physical templates such as extracellular matrix proteins which may direct cell migration. Additionally, elaboration of growth-promoting, growth-inhibiting, or differentiating factors may play a role. These signals are important for the development and maintenance of normal tissue architecture during embryogenesis and during tissue regeneration following injury in the adult. The tissue model utilized in this research is normal human neonatal skin. Many events in normal skin development rely upon the exchange of information between epidermal keratinocytes and dermal cell types. The specific events and regulatory factors that mediate dermal-epidermal interactions are currently unknown. Questions addressed in the research proposal are: (1) Do growth stimulatory factors for human keratinocytes (epidermal growth factor and keratinocyte growth factor) or growth inhibitory factors (transforming growth factor-betas) affect synthesis of basement membrane components (collagen types IV, VII, or fibronectin)? (2) Do TGF-betas affect cell type-specific terminal differentiation markers in human keratinocytes? For example, is transcription of the gene for a cornified envelope precursor, involucrin, enhanced by TGF-beta-1 or -beta-2? (3) Does loss of substratum attachment trigger expression of keratinocyte TGF-betas? (4) Can fibronectin or other basement membrane components induce expression of involucrin mRNA in human keratinocytes? (5) Do the extracellular matrices synthesized by dermal fibroblasts exposed to growth regulatory factors affect the growth or differentiation properties of epidermal keratinocytes? The immediate goal is to gain information on the role that ECM and diffusible factors, such as TGF-betas, play in normal human epidermal differentiation. These studies will generate fundamental information that will aid in understanding and treatment of developmentally caused skin malformations. In addition, these studies may be important for strategies to develop optimal dermal equivalents for the coverage of large wound areas. Knowledge of the effects of extracellular matrix glycoproteins on the differentiation characteristics of epidermal keratinocytes will facilitate the formulation of dermal equivalents.