Dr. Engelhard is interested in the molecular mechanisms underlying growth control and differentiation, which when altered lead to pathologies of the skin.  Mutations in the hairless (hr) gene, which cause alopecia in mice and atrichia with papular lesions (APL) in humans, result in aberrant apoptosis and morphologic changes in the structure of the hair follicle that have been characterized, yet little is known about the regulation of hr expression or the molecular mechanism disrupted by hr mutations. Several lines of evidence suggest that HR functions as a transcription factor of the zinc finger type, yet this function has never been demonstrated.  1) An Hr domain shares homology with the GATA-1 zinc finger domain, which is responsible for DNA binding.  2) A point mutation in an APL patient results in the substitution of glycine for a conserved, presumably zinc-coordinating cysteine residue at amino acid 622.  3) Hr mutations result in the complete loss of functional hair follicles, and 4) Hr localizes to the nucleus.  Dr. Engelhard is using random oligonucleotide selection and amplification, a procedure known as CASTing, to demonstrate that Hr is a zinc finger transcription factor by identifying a unique consensus sequence to which Hr binds and assaying the ability of this sequence to act as a Hairless Response Element when incorporated into the sequence of promoters.  Having also cloned the hr promoter, Dr. Engelhard has demonstrated the differential regulation of the hairless gene promoter by thyroid hormone T3.  The thyroid hormone response element first identified in the rat hr promoter is functional in a neuronal cell types but not in keratinocyte cell lines.  He is using molecular dissection to identify the unique elements which coordinate hairless expression in the hair cycle and to identify the molecules with which these elements interact.