The applicant's long-term goal is to direct a basic science research program exploring the role of endothelial cells and their progenitors in organ fibrosis and tumor progression. The applicant has been trained in somatic stem cell biology during her thesis work and was later able to apply this knowledge in cardiovascular research where she was additionally trained in embryonic stem cell biology. During the first part of a postdoctoral fellowship, the applicant expanded her knowledge on stem cell biology and gained new insights into embryonic development. During these studies, the applicant became interested in the cellular plasticity that is displayed by endothelial cells both during embryonic development and also in adult disease states. The applicant is now an Instructor in Medicine in the Kalluri laboratory, where both tumor angiogenesis and organ fibrosis are major research foci, and thus it was a natural extension of the applicant's interests to study endothelial cell plasticity in the setting of the tumor microenvironment. The applicant's previous studies for the first time demonstrated that in cardiac fibrosis endothelial cells contribute to the pool of fibroblasts via an endothelial transition and that inhibition of EndMT can lead to decreased fibrosis and improved cardiac function. The research project proposed here centers on testing the hypothesis that EndMT also plays a role in tumor fibrogenesis. This hypothesis is based on immunohistochemical staining which revealed cells that are double positive for both endothelial and fibroblasts in several tumor types, indicating that endothelial cells can undergo EndMT. The primary aim of the proposal is to provide genetic evidence that endothelial cells contribute to the fibroblast population in the tumor microenvironment by undergoing EndMT. For this purpose, endothelial lineage tracing by TielCre;R26RstoplacZ double transgenic mice, in which all cells of endothelial origin are irreversibly marked with lacZ, will be used. Second, the impact of EndMT on tumor progression will be evaluated by creating transgenic mice in which fibroblasts of endothelial origin will be selectively ablated. If the tested hypothesis is valid, EndMT might represent an important target for the treatment of cancer.
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