Competent lactation is essential for mammalian survival and the sustenance of many human populations. Breastfeeding is mutually beneficial for both mothers and infants. Mammary development to achieve lactational competence is regulated by hormones, growth factors and proteinases. However, the identity of these elements and how they interact to effect mammary development are not fully understood. Previous studies have documented a partial lactational defect in plasminogen deficient mice. A critical gap in knowledge is how components of the plasminogen activation system regulate lactation. The plasminogen receptor, Plg-RKT, is a novel integral membrane protein that binds plasminogen and promotes plasminogen activation on cell surfaces. The broad, long-term goal of our laboratory is to understand mechanisms by which Plg-RKT regulates physiologic and pathologic processes. This proposal is based on our data demonstrating complete absence of lactational competence, resulting in death of all offspring of Plg-RKT deficient female mice. In addition to a defect in fibrinolysis, Plg-RKT deficiency also leads to severe defects in mammary gland development that do not take place in plasminogen deficient mice. We propose to extend these discoveries toward a new direction by performing exploratory/developmental studies. The objective of this proposal is to elucidate plasminogen- independent mechanisms by which Plg-RKT regulates lactation. The central hypothesis to be addressed is that Plg-RKT is expressed by specific mammary cell types that function to regulate lactational development via both plasminogen-dependent and plasminogen-independent mechanisms. To address our hypothesis, our specific aims are: 1) to distinguish plasminogen-independent and -dependent functions of Plg-RKT in lactational development; and 2) to identify ligands, in addition to plasminogen, that interact with Plg-RKT. Studies will be carried out in Plg-RKT-/- mice and in mice harboring a PLGRKT transgene incapable of binding plasminogen. We expect that accomplishment of our specific aims will provide fundamental insights into new mechanisms by which lactational development is regulated. The results obtained may also lead in the future to understanding biological mechanisms through which suboptimal lactation affects the risk for cardiovascular disease and cancer in women. These studies also have high relevance for understanding the basis of mammary fibrosis, a key process in fibrocystic breast disease. New insights resulting from these studies are also expected to have a major impact on our understanding of a broad array of pathological and physiological processes in organs that undergo post-embryonic morphogenesis in response to injury, including kidney and prostate. Performance of the proposed experiments is expected to suggest new targets and cell-based assays that potentially can be used to screen for agonists that may promote Plg-RKT function and/or expression to promote lactation, to treat mammary fibrosis, and to treat diseases involving dysregulated post-embryonic morphogenesis.
The proposed research is relevant to public health because new knowledge of mechanisms by which lactation is regulated will be acquired and competent lactation is essential for mammalian survival and the sustenance of many human populations and breastfeeding is mutually beneficial for both mothers and infants, providing children with numerous health benefits and may play a role in protecting mothers against development of breast cancer and future cardiovascular disease. This knowledge to be obtained is directly applicable to understanding the basis of mammary fibrosis, a key process in development of fibrocystic breast disease, as well understanding of a broad array of pathological and physiological processes in organs that undergo post- embryonic morphogenesis in response to injury including kidney, prostate, lacrimal gland, and salivary gland and may also lead in the future to understanding biological mechanisms through which suboptimal lactation affects the risk for cardiovascular disease and cancer in women. Furthermore, performance of the proposed experiments is expected to suggest new targets and cell-based assays that can be used to screen for agonists that may stimulate Plg-RKT function and/or expression to promote lactation in mothers with low epithelial expression of Plg-RKT, to treat mammary fibrosis, and, in general, to treat diseases involving dysregulated tissue remodeling.
