Receptor tyrosine kinase (RTK) is a major signaling pathway regulating formation and homeostasis of vertebrate organs in which branching morphogenesis occurs. Deregulated RTK signaling is a primary cause of many human congenital diseases and postnatal illnesses concerning these organs. The long term goal of this application is to understand the role of RTK signaling pathway in epithelium-stroma interactions and how RTK signaling is regulated at different stages to ensure normal development of the mammary gland. The investigator hypothesizes that function of RTK signaling is required both in the mammary epithelium and in the stroma to control various aspects of mammary gland development. This hypothesis is based on the investigator's recent findings showing that function of FGF receptor 2, an RTK expressed in the epithelium, is essential for epithelial invasion, as well as loss of SPRY1, an inhibitor of RTK signaling, causes branching defects suggestive of excess RTK signaling activity in the stroma. Thus, Specific Aim 1 is to analyze the role of FGFR2 in the mammary epithelium during postnatal branching morphogenesis. It has been found that Fgfr2 function is required in the end buds to promote cell proliferation during epithelial invasion. Other roles that Fgfr2 may also play, for example in directing epithelial migration, will also be examined.
Specific Aim 2 is to analyze the role of FGFR2 in mammary gland stem cell renewal and differentiation. The investigator will determine the role of FGF signaling, which plays a role in various invertebrate and vertebrate stem cell systems, in development mammary gland stem cells. Effects of loss of FGF signaling activities by removing Fgfr2 on mammary stem cells will be examined.
Specific Aim 3 is to analyze the normal mechanism of RTK signaling regulation by Spry1 in the stroma during mammary gland branching morphogenesis. Although well-known for its role in normal epithelial development and in breast tumorigenesis, the molecular basis of the stroma microenvironment has remained largely unclear. In this study, the investigator will characterize defects caused by loss of Spry1 function, identify the RTK pathways regulated by Spry1, and determine whether the stroma may play a role in mammary stem cell development.
Branching morphogenesis is the process whereby many vertebrate epithelial organs, including the vasculature, lung, mammary gland, and kidney, form during development. This study addresses the role of receptor tyrosine kinase (RTK) signaling in branching morphogenesis of the mammary gland by focusing on function of FGF signaling in epithelial migration and in mammary stem cell maintenance as well as how RTK signaling is regulated by Spry1, an antagonist of RTK signaling, during mammary gland development. If deregulation of RTK signaling could be prevented then we would greatly improve therapeutic interventions of human congenital illnesses inflicting the above epithelial organs and save the lives of millions of patients.
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