During pregnancy, the mammary gland undergoes morphological and biochemical changes to achieve final secretory differentiation. Failure to accomplish these changes is known to result in lactational failure - a problem for 3-15% of breastfeeding mothers. A potential model for the morphological and biochemical events associated with secretory activation is the whey acidic protein (WAP)/human protein C (hPC) transgenic mice. These mice exhibited small alveoli, impaired luminal expansion, reduced milk protein gene expression, and failed to lactate. The mammary epithelial cells had distinct, centrally located nuclei and contained large cytoplasmic lipid droplets associated with functionally inactive glands. A pilot microarray analysis of WAP/hPC mouse mammary gland RNA revealed significant (10 fold) upregulation of a transcriptional repressor protein called translocated ets leukemia (TEL). There is evidence to suggest that TEL transcription and activity is repressed during proliferation, and its overexpression may be linked to impaired tissue remodeling. I propose that homozygous expression of the WAP/hPC transgene aberrantly elevates TEL expression in alveolar epithelial cells, repressing their normal proliferation and differentiation and leading to a failure to lactate. The goal of this proposal is to define the role of TEL in generating the defects seen in WAP/hPC mice as well as its role in normal mammary gland development.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32HD044359-03
Application #
6870194
Study Section
Special Emphasis Panel (ZRG1-F06 (20))
Program Officer
Grave, Gilman D
Project Start
2003-04-18
Project End
2006-04-17
Budget Start
2005-04-18
Budget End
2006-04-17
Support Year
3
Fiscal Year
2005
Total Cost
$49,928
Indirect Cost
Name
University of Colorado Denver
Department
Physiology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Russell, Tanya D; Palmer, Carol A; Orlicky, David J et al. (2008) Mammary glands of adipophilin-null mice produce an amino-terminally truncated form of adipophilin that mediates milk lipid droplet formation and secretion. J Lipid Res 49:206-16
Russell, Tanya D; Palmer, Carol A; Orlicky, David J et al. (2007) Cytoplasmic lipid droplet accumulation in developing mammary epithelial cells: roles of adipophilin and lipid metabolism. J Lipid Res 48:1463-75
Palmer, Carol A; Neville, Margaret C; Anderson, Steven M et al. (2006) Analysis of lactation defects in transgenic mice. J Mammary Gland Biol Neoplasia 11:269-82