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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA129204-03
Application #
7846164
Study Section
Subcommittee G - Education (NCI)
Program Officer
Myrick, Dorkina C
Project Start
2008-06-01
Project End
2013-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
3
Fiscal Year
2010
Total Cost
$135,270
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Charytan, David M; Helfand, Alexander M; MacDonald, Brian A et al. (2011) Circulating endoglin concentration is not elevated in chronic kidney disease. PLoS One 6:e23718
Bechtel, Wibke; McGoohan, Scott; Zeisberg, Elisabeth M et al. (2010) Methylation determines fibroblast activation and fibrogenesis in the kidney. Nat Med 16:544-50
Zeisberg, Elisabeth M; Kalluri, Raghu (2010) Origins of cardiac fibroblasts. Circ Res 107:1304-12
Krenning, Guido; Zeisberg, Elisabeth M; Kalluri, Raghu (2010) The origin of fibroblasts and mechanism of cardiac fibrosis. J Cell Physiol 225:631-7
Zeisberg, Elisabeth M; Potenta, Scott E; Sugimoto, Hikaru et al. (2008) Fibroblasts in kidney fibrosis emerge via endothelial-to-mesenchymal transition. J Am Soc Nephrol 19:2282-7
Potenta, S; Zeisberg, E; Kalluri, R (2008) The role of endothelial-to-mesenchymal transition in cancer progression. Br J Cancer 99:1375-9