Lactation is critical to survival of all mammals because it supports the growth of the newborn. Successful lactation requires completion of all developmental stages proceeding lactation, including pubertal development largely stimulated by estrogen, expansion of the secretory alveoli in early pregnancy driven by progesterone and prolactin, secretory differentiation occurring during late pregnancy, and secretory activation that occurs at parturition. A failure at any stage often results in ineffective lactation, indicated by either inadequate growth or death of newborns. Despite substantive advances in mammary gland biology, substantial gaps in our understanding of lactation exist. While great advances have been made regarding regulation of milk protein genes, our understanding of lipid biosynthesis has lagged behind. During the last ten years our group at the University of Colorado School of Medicine, has focused on secretory differentiation and activation with an increasing focus upon lipid metabolism and synthesis of lipid component of milk. The overarching hypothesis of this program project grant is that mammary gland development is not controlled by a single master controller gene, but rather a carefully patterned progression of """"""""genetic regulators"""""""" that control development during mid-pregnancy, late pregnancy, and secretory activation. In Project I we will examine the role of Aktl in regulating the """"""""lipid switch"""""""" that occurs at secretory activation- the coordinate transcriptional activation of enzymes involved in lipid biosynthesis. In Project II we will examine the role of progesterone and insulin in alveolar development during pregnancy. In Project III we will examine the role of microRNAs in mammary gland development with particular focus on their ability to modulate metabolic changes and signaling by steroid hormone receptors. In Project IV we will focus on how formation of cytoplasmic lipids droplets is regulated. These projects are assisted by two Cores: an Administrative Core that oversees fiscal issues and provides logistic support and the Adenovirus Core that prepares recombinant human adenoviral vectors for use in the projects. This concerted effort will provide mechanistic underpinnings for understanding lactation failure in women related to diabetes and/or obesity.

Public Health Relevance

Obesity has reached epidemic status in the US and increases the risk of type II diabetes. Both obese and diabetic women have difficulty initiating and sustaining lactation;therefore it is important to identify measures that improve breastfeeding in these women. Our research focuses on how insulin, progesterone, Akt, and microRNAs regulate development and function of the normal mammary gland, which may provide insight to thfi metabolic dysfunction of impaired lactation in obese and diabetic women.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD038129-13
Application #
8511740
Study Section
Special Emphasis Panel (ZHD1-DSR-Z (AS))
Program Officer
Grave, Gilman D
Project Start
2001-06-01
Project End
2016-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
13
Fiscal Year
2013
Total Cost
$970,833
Indirect Cost
$288,117
Name
University of Colorado Denver
Department
Pathology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Treviño, Lindsey S; Bolt, Michael J; Grimm, Sandra L et al. (2016) Differential Regulation of Progesterone Receptor-Mediated Transcription by CDK2 and DNA-PK. Mol Endocrinol 30:158-72
Sladek, Celia D; Stevens, Wanida; Song, Zhilin et al. (2016) The ""metabolic sensor"" function of rat supraoptic oxytocin and vasopressin neurons is attenuated during lactation but not in diet-induced obesity. Am J Physiol Regul Integr Comp Physiol 310:R337-45
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Rudolph, Michael C; Wellberg, Elizabeth A; Lewis, Andrew S et al. (2014) Thyroid hormone responsive protein Spot14 enhances catalysis of fatty acid synthase in lactating mammary epithelium. J Lipid Res 55:1052-65
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McManaman, James L (2014) Lipid transport in the lactating mammary gland. J Mammary Gland Biol Neoplasia 19:35-42
Wellberg, Elizabeth A; Anderson, Steven M (2014) FASNating targets of metformin in breast cancer stem-like cells. Horm Cancer 5:358-62

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