Normal human keratinocytes secrete a parathyroid hormone-like peptide (PTH-LP) in vitro. The keratinocyte PTH-LP appears to be derived from the same gene as the recently cloned cDNA for a tumor-derived PTH-LP associated with the clinical syndrome of humoral hypercalcemia of malignancy. The normal function of this peptide is not known: the factors regulating its expression in vivo are not known. The long-term objectives of this proposal are: 1) to determine whether and how production of this molecule is regulated in keratinocytes; 2) to identify the function(s) of this molecule in the skin and elucidate the mechanism(s) by which it acts: 3) to determine whether there is a relationship between diseases of the skin and abnormal expression of this molecule.
These aims and hypotheses will be investigated in tissue sections and in tissue culture models of epidermal growth and differentiation and will employ specific molecular and immunologic probes for the PTH-LP. The specific questions are: Production regulations: a. Which keratinocyts within the epidermis make and secrete the PTH-LP? b. Are there physiologic or pharmacologic ways to regulate production of the PTH-LP by keratinocytes? c. What is the molecular basis of regulated production? Is production regulated at the level of transcription, splicing, translation, intracellular processing or secretion? Function/mechanism of action: a. What effect does the PTH-LP have on normal keratinocyte growth and differentiation and what mediates that effect? Hypothesis: The autocrine action of the PTH-LP acts via an increase in intracellular calcium which then triggers or augments differentiation. b. What are its effects on dermal fibroblasts? Hypothesis: The molecule plays a role in dermal remodelling via its TGF-b like action on secretion on connective tissue elements. Relation to disease: a. Is the PTH-LP overexpressed in neoplastic diseases of the epidermis or in benign hyperproliferative diseases? If so, is the PTH-LP detectable in the serum? b. If the molecule has a role in normal keratinization, are there disorders of keratinization caused by abnormal production of or response to the PTH- LP?
