Candidate: I am a pediatric plastic surgeon with an interest in Vascular Anomalies, and a member of Columbia University's multi-disciplinary Vascular Anomalies Group. My clinical expertise includes treating children, affected by hemangiomas and vascular malformations, which allows access to resected clinical specimens that can be used for research. I am interested in studying normal and abnormal vasculogenesis and angiogenesis in hemangiomas, specifically Notch signaling in hemangiomas, since Notch is known to play a role in vasculogenesis and angiogenesis. I was able to secure support and mentorship from Dr. Jan Kitajewski, a vascular biologist studying Notch and Dr. Joyce Bischoff, a hemangioma expert. With their support and guidance, I was able to show, for the first time, that Notch genes were expressed in hemangiomas in an intriguing pattern. As a clinician who specializes in Vascular Anomalies, I am in a unique position to observe the clinical behavior of these lesions and bring research ideas to fruition through a Career Development Award, i.e., from bedside to the bench, and to design and conduct basic science research independently. In addition, if awarded, I will also plan to attend classes on conducting responsible clinical research and biostatistics, so that I can apply what I learn in the laboratory-from bench to bedside-to design clinical trials to improve treatment options for children with problematic hemangiomas. Environment: Columbia University and New York Presbyterian Hospital has a free-standing Children's Hospital and specializes in treating the pediatric population in a variety of diseases and conditions. With our Vascular Anomalies Group, we have a steady patient referral base. Moreover, I have research space both with the Department of Surgery, as well as space with Dr. Kitajewski's laboratory in the Irving Cancer Research Center. Dr. Kitajewski's laboratory has the necessary equipment and facilities necessary to conduct Notch signaling research. Moreover, there will be ample opportunities to interact with graduate and post-graduate research fellows in his laboratory, both in formal laboratory meetings and informally at the bench. Dr. Kitajewski's laboratory is physically connected to Drs. Kandel and Yamashiro's laboratory, who are on my advisory committee. Columbia University holds many seminars and conferences, from molecular biology to responsible research conduct. Therefore, Columbia University is the ideal place to train as a clinician scientist. Research: Infantile hemangiomas (IHs) are the most common benign tumors of infancy. They have a unique life cycle: from rapid proliferation followed by involution. Despite being """"""""benign"""""""" lesions, they can cause significant, possibly irreversible, morbidity during proliferation, including life-threatening respiratory compromise, blindness, hemorrhage, and ulceration. Infants with large, segmental facial hemangiomas as part of the PHACES syndrome are at risk for strokes. There is currently no FDA-approved treatment for problematic IHs, in part due to limited understanding of the origin and regulation of IHs, and lack of an animal model until recently. Therefore, development of targeted therapy for problematic hemangiomas has been hampered. Recent studies have shown that the hemangioma stem cell (HemSC) as the origin of hemangiomas, a highly proliferative cell, which then differentiates to an endothelial fate (HemEC)(Khan, Boscolo et al. 2008). Other cell types are also known to be present in hemangiomas, including pericytes, which have never been isolated from a hemangioma(Boscolo and Bischoff 2009) but may arise from HemSC as well. It is known that endothelial cell and pericyte interactions are vital to formation of blood vessels. Work in our laboratory has shown that Notch3 is expressed in HemSCs, but not HemECs nor human dermal microvascular endothelial cells (HDMECs). Notch3, however, is known to be expressed by perictyes and play a role in blood vessel formation via Notch3 regulation(Liu, Kennard et al. 2009). Our hypothesis is that proliferation and involution in hemangiomas is controlled by Notch3 activity, and Notch3 expression is not required or must be turned off for HemSC to differentiate into HemEC. We hypothesize that Notch3 also play a role in the differentiation of HemSC to perictyes in hemangiomas. We have 3 specific aims to address these questions. The first will focus on the role of Notch3 in helping to maintain HemSCs in their capacity to proliferate and grow.
The second aim to isolate and characterize Notch3-positive pericytes in hemangiomas. Finally, we aim to study the effects of activating Notch3 activity in HemEC, to see whether we can force the HemEC to become more like a HemSC or a pericyte. Boscolo, E. and J. Bischoff (2009). """"""""Vasculogenesis in infantile hemangioma."""""""" Angiogenesis. Khan, Z. A., E. Boscolo, et al. (2008). """"""""Multipotential stem cells recapitulate human infantile hemangioma in immunodeficient mice."""""""" J Clin Invest. Liu, H., S. Kennard, et al. (2009). """"""""NOTCH3 expression is induced in mural cells through an autoregulatory loop that requires endothelial-expressed JAGGED1."""""""" Circ Res 104(4): 466-75.
This proposal will study the regulation of HemSC and HemEC by NOTCH3 in hemangiomas, potentially giving us a therapeutic target for treating proliferating, problematic hemangiomas. Moreover, it will help provide insights to normal and abnormal blood vessel formation, and the interaction between a stem cell, and endothelial cell, and a pericyte in formation of blood vessels.
