The overall scientific goal of this proposal is to investigate mechanisms which control parathyroid hormone-related protein (PTHrP) mRNA expression and secretion in normal and neoplastic keratinocytes. It is hypothesized that there are important differences in the pathophysiology of PTHrP regulation in normal compared to neoplastic keratinocytes. PTHrP mRNA will likely be expressed in a manner regulated by differentiation in normal keratinocytes and will demonstrate polarity of secretion (away from the dermis). In contrast, neoplastic keratinocytes likely have altered regulation of PTHrP mRNA expression and secretion and will not demonstrate polarity of secretion. The proposal has three objectives: (1) investigate the regulation of PTHrP mRNA expression (steady state levels and in situ localization), transcription rate, and stability by cytokines (TGFalpha, TGFbeta, and IL-1), 1,25-dihydroxyvitamin D, and calcium in normal human keratinocytes and squamous cell carcinoma cell lines grown in monolayer and 3-dimensional cell cultures, (2) investigate the regulation and polarity of PTHrP secretion by agents which affect protein kinase C and intracellular calcium, by inhibitors/stimulators of vesicular secretion, and by the presence of basement membrane components, and (3) determine the relationship of PTHrP mRNA expression with the regulation of tissue-specific gene expression during keratinocyte proliferation (c-myc and H3 histone genes) and differentiation (involucrin, filaggrin, and keratin 1 and 6 genes). The use of 3-dimensional cell cultures will be an important aspect of the investigations and will permit normal differentiation of epidermal keratinocytes in vitro and allow comparisons with neoplastic keratinocytes. Information on the cellular biology of PTHRP is necessary to determine its role in the pathologic state of CAH, its role in the normal physiology of epithelial cells, and mechanisms by which its secretion and synthesis can be controlled.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Modified Research Career Development Award (K04)
Project #
5K04AR001923-02
Application #
2077482
Study Section
General Medicine B Study Section (GMB)
Project Start
1993-08-01
Project End
1998-07-31
Budget Start
1994-08-01
Budget End
1995-07-31
Support Year
2
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Ohio State University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
098987217
City
Columbus
State
OH
Country
United States
Zip Code
43210
Blomme, E A; Zhou, H; Kartsogiannis, V et al. (1999) Spatial and temporal expression of parathyroid hormone-related protein during wound healing. J Invest Dermatol 112:788-95
Blomme, E A; Dougherty, K M; Pienta, K J et al. (1999) Skeletal metastasis of prostate adenocarcinoma in rats: morphometric analysis and role of parathyroid hormone-related protein. Prostate 39:187-97
Blomme, E A; Sugimoto, Y; Lin, Y C et al. (1999) Parathyroid hormone-related protein is a positive regulator of keratinocyte growth factor expression by normal dermal fibroblasts. Mol Cell Endocrinol 152:189-97
Wojcik, S F; Capen, C C; Rosol, T J (1999) Expression of PTHrP and the PTH/PTHrP receptor in purified alveolar epithelial cells, myoepithelial cells, and stromal fibroblasts derived from the lactating rat mammary gland. Exp Cell Res 248:415-22
Werkmeister, J R; Blomme, E A; Weckmann, M T et al. (1998) Effect of transforming growth factor-beta1 on parathyroid hormone-related protein secretion and mRNA expression by normal human keratinocytes in vitro. Endocrine 8:291-9
Blomme, E A; Werkmeister, J R; Zhou, H et al. (1998) Parathyroid hormone-related protein expression and secretion in a skin organotypic culture system. Endocrine 8:143-51
Wojcik, S F; Schanbacher, F L; McCauley, L K et al. (1998) Cloning of bovine parathyroid hormone-related protein (PTHrP) cDNA and expression of PTHrP mRNA in the bovine mammary gland. J Mol Endocrinol 20:271-80
Blomme, E A; Weckmann, M T; Capen, C C et al. (1998) Influence of extracellular matrix macromolecules on normal human keratinocyte phenotype and parathyroid hormone-related protein secretion and expression in vitro. Exp Cell Res 238:204-15
Grone, A; Weckmann, M T; Blomme, E A et al. (1998) Dependence of humoral hypercalcemia of malignancy on parathyroid hormone-related protein expression in the canine anal sac apocrine gland adenocarcinoma (CAC-8) nude mouse model. Vet Pathol 35:344-51
Blomme, E A; Sugimoto, Y; McCauley, L K et al. (1998) Stromal and epithelial cells of the canine prostate express parathyroid hormone-related protein, but not the PTH/PTHrP receptor. Prostate 36:110-20

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