PDGF Receptor Signaling in Mammalian Development

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DESCRIPTION (provided by applicant): Platelet derived growth factor receptors (PDGFRa and PDGFRa) are receptor tyrosine kinases that play an important role in the development and function of many mesenchymal cell types including vascular smooth muscle cells and lung alveolar smooth muscle cells. When these receptors bind ligand, they are capable of activating a multitude of signal transduction pathways within the cell, resulting in proliferation, differentiation, and migration. Although the receptors' signal transduction has been studied for many years, their roles in vivo remain elusive. The long term goals of this proposal are to understand how these signal transduction pathways translate to cellular responses and apply this knowledge to understanding the function of this family of receptors in vascular biology and mesenchymal cell development. To attain this goal, a panel of mice that afford the unique opportunity to investigate signal transduction in living tissues has been generated. These mice will be used in a series of experiments designed to address the role of biochemical signals in the heart, the kidney, and the eye. The specific aims of this proposal are to: 1) study the function of the PDGFRa in development and signal transduction of mural cells (vascular smooth muscle cells and pericytes); and 2) identify the function of phosphoinositide-3 kinase downstream of both PDGF receptors during mammalian embryogenesis. The knowledge gained from these studies will provide essential information regarding the mechanisms of receptor mediated intracellular signal transduction within mammalian tissues. In addition, these experiments will offer necessary details regarding the function of PDGF receptors in mesenchymal cells especially those that provide support for blood vessels. This understanding could lead to novel approaches for controlling this cell population during development and in disease states.