Humoral hypercalcemia of malignancy is a common paraneoplastic syndrome. The peptide factor or factors mediating this syndrome has not been previously identified. The two most active hypotheses at present are that the factor in question is a parathyroid hormone-like peptide or a growth factor-peptide. In ongoing studies, we have 1) fully characterized a number of animal models of the humoral syndrome and have identified a similar factor as a secretary product of normal keratinocytes, 2) purified and sequenced peptides from a human and a rat tumor, with the human tumor peptide revealing an aminoterminal region of striking homology to human parathyroid hormone, 3) constructed a cDNA library from a renal human carcinoma mRNA, and 4) begun to study the actions of the tumor-derived peptide at the level of its two key target tissues, bone and kidney. The principle goals of the present proposal include: 1) to continue our purification and sequencing efforts using tumors from humans and several other species, 2) to develop polyclonal and monoclonal antibodies to the human and rat peptides, 3) to identify and sequence a fulllength cDNA and initiate a broad range of molecular projects, and 4) to expand and refine out studies of the factor's actions on bone and renal cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR030102-11
Application #
3155747
Study Section
General Medicine B Study Section (GMB)
Project Start
1981-07-01
Project End
1992-06-30
Budget Start
1991-07-01
Budget End
1992-06-30
Support Year
11
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Yale University
Department
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Brines, M L; Ling, Z; Broadus, A E (1999) Parathyroid hormone-related protein protects against kainic acid excitotoxicity in rat cerebellar granule cells by regulating L-type channel calcium flux. Neurosci Lett 274:13-6
Philbrick, W M; Dreyer, B E; Nakchbandi, I A et al. (1998) Parathyroid hormone-related protein is required for tooth eruption. Proc Natl Acad Sci U S A 95:11846-51
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Philbrick, W M (1998) Parathyroid hormone-related protein is a developmental regulatory molecule. Eur J Oral Sci 106 Suppl 1:32-7
Amling, M; Neff, L; Tanaka, S et al. (1997) Bcl-2 lies downstream of parathyroid hormone-related peptide in a signaling pathway that regulates chondrocyte maturation during skeletal development. J Cell Biol 136:205-13
Vasavada, R C; Cavaliere, C; D'Ercole, A J et al. (1996) Overexpression of parathyroid hormone-related protein in the pancreatic islets of transgenic mice causes islet hyperplasia, hyperinsulinemia, and hypoglycemia. J Biol Chem 271:1200-8
Philbrick, W M; Wysolmerski, J J; Galbraith, S et al. (1996) Defining the roles of parathyroid hormone-related protein in normal physiology. Physiol Rev 76:127-73

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