NOTCH IN PATHOLOGICAL ANGIOGENESIS AND LYMPHANGIOGENESIS

Training PlanI entered the doctoral Pharmacology program at Columbia University Medical Center with a strong interest in tumor biology, particularly in the field of breast cancer research. I am pursuing my interest in the lab of Dr. Jan Kitajewski, which focuses on angiogenesis. Upon completion of my training as a graduate student, my plan is to continue in breast cancer research, whether it be as a postdoctoral candidate at a university, a researcher in a government institution, or in industry. My proposed training plan is the study of lymphangiogenesis and angiogenesis in a pathological context, that is, in breast cancer. My goal is to become an expert in (lymph)angiogenesis in breast cancer, and for my research to one day be used in the development breast cancer treatments. Receiving this year's Department of Defense Breast Cancer Predoctoral Fellowship would allow me to truly delve into my research. Additionally, as a recipient I would be able to attend training sessions, workshops, and conferences that would augment my training at the bench. Attending and presenting at the Era of Hope meeting would be a particularly important opportunity, as it would allow me to share my research with others who have the same research goals. Having representation from breast cancer survivors would provide perspectives that normally are not considered at most scientific meetings.Research PlanBackground: Breast cancer is one of the top causes of mortality in women. More often than not, malignancy is a result of invasiveness and metastasis. Lymphangiogenesis and angiogenesis have been implicated as key players in the growth and metastasis of breast cancer. The Notch signaling pathway has been shown to play an important role in (lymph)angiogenesis, which may in turn affect the growth and metastasis of tumors.Hypothesis: Activation of different Notch proteins appear to have different effects on tumor (lymph)angiogenesis, either suppressing or inducing tumor growth. Therefore, we hypothesize that distinct Notch proteins may play different roles in (lymph)angiogenesis. Inhibition of those Notch proteins that activate (lymph)angiogenesis may suppress tumor (lymph)angiogenesis in a breast cancer model, thereby inhibiting tumor growth and/or metastasis.Aims: I: Study how Notch signaling functions in primary lymphatic endothelial cells (LECs). II: Study Notch function in pathological lymphangiogenesis. III: Study Notch function in pathological angiogenesis.Study Design: I: Different proteins in the proposed Notch signaling pathway will be activated or inactivated to observe effects on in vitro LEC behavior and downstream LEC markers. II: Mouse models of breast cancer will be used with two different human breast cancer cell lines, and effects on lymphangiogenesis will be observed upon inhibition of Notch signaling. III: Mouse models of breast cancer will be used with two different human breast cancer cell lines, and effects on angiogenesis will be observed upon inhibition of Notch signaling.