The Notch pathway is a conserved signaling mechanism that functions to modulate cell- fate decisions. The overall objectives of this proposal are to define roles for Notch in cell- fate determination during lymphatic remodeling, and tumor lymphangiogenesis. Our general hypothesis is that Notch activity is necessary to assist in lymphatic remodeling. We hypothesize unique roles for different Notch family members in lymphatic growth and development, with a focus on Notch1, Notch3, and Notch4. We have discovered that VEGFR-3, a lymphatic regulator, is transciptionally regulated by Notch1 and Notch4. In contrast, a complex regulation of Prox-1 by Notch was uncovered with opposing roles for Notch1 and Notch4. Our general strategy will use a combination of in vitro lymphangiogenesis assays and mouse modeling to define the consequences of altering Notch activity in lymphatic endothelial cells. In addition, our preliminary studies implicate Notch as a regulator of tumor lymphatic growth and a factor controlling VEGFR-3 expression in tumor vessels and lymphatics.
In Aim I, we evaluate Notch function in isolated lymphatic endothelial cells with the goal of determining if Notch regulation of VEGFR-3 and Prox1 is key to lymphatic endothelial cell behavior.
In Aim II, we will analyze Notch mutant mice and activate Notch in dermal lymphatic endothelial cells to determine if Notch promotes lymphangiogenesis, lymphatic remodeling or lymphatic integrity.
In Aim III, we use a Notch inhibitor developed in the lab, a secreted antagonist of ligand-dependent Notch signaling, to evaluate if VEGF-C-mediated tumor lymphangiogenesis requires Notch. Our overall goal is to study both developmental and pathological lymphangiogenesis to better understand Notch function in lymphatics.

Public Health Relevance

Notch signaling is fundamental to proper vascular development. We present data strongly implicating Notch as a regulator of lymphatic development and pathologies. Thus, the studies outline in our proposal will aid us in understanding the functions of Notch in lymphatic differentiation and may be critical to developing strategies and therapeutics to correct lymphatic disorders or block tumor lymphangiogenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA136673-04
Application #
8255358
Study Section
Special Emphasis Panel (ZRG1-CVS-P (50))
Program Officer
Woodhouse, Elizabeth
Project Start
2009-06-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
4
Fiscal Year
2012
Total Cost
$324,053
Indirect Cost
$122,778
Name
Columbia University (N.Y.)
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Murtomaki, Aino; Uh, Minji K; Kitajewski, Chris et al. (2014) Notch signaling functions in lymphatic valve formation. Development 141:2446-51
England, Ryan W; Hardy, Krista L; Kitajewski, Alex M et al. (2014) Propranolol promotes accelerated and dysregulated adipogenesis in hemangioma stem cells. Ann Plast Surg 73 Suppl 1:S119-24
Douglas, Nataki C; Zimmermann, Ralf C; Tan, Qian Kun et al. (2014) VEGFR-1 blockade disrupts peri-implantation decidual angiogenesis and macrophage recruitment. Vasc Cell 6:16
Murtomaki, Aino; Uh, Minji K; Choi, Yun K et al. (2013) Notch1 functions as a negative regulator of lymphatic endothelial cell differentiation in the venous endothelium. Development 140:2365-76
Shah, Monjri M; Zerlin, Marielba; Li, Blake Y et al. (2013) The role of Notch and gamma-secretase inhibition in an ovarian cancer model. Anticancer Res 33:801-8
Outtz, Hasina Hamilton; Wu, June K; Wang, Xing et al. (2010) Notch1 deficiency results in decreased inflammation during wound healing and regulates vascular endothelial growth factor receptor-1 and inflammatory cytokine expression in macrophages. J Immunol 185:4363-73