Pathological angiogenesis is a key process that drives vascular remodeling in numerous cardiovascular and metabolic diseases including diabetic retinopathy and cancer. However, due to the lack of appropriate targets, limited effective medicines or therapies to treat this pathological process are available. Epsins were originally identified by the PI as a family of important endocytic adaptor proteins. We recently showed that epsins, via their ubiquitin-interacting motifs (UIM), are critical for activated VEGFR2 internalization, degradation and signal attenuation. Intriguingly, endocytosis of activated VEGFR2 by a different endocytic adaptor protein, Dab2, results in enhanced VEGF signaling. How VEGFR2 internalization differentially modulates VEGF signaling is a highly significant and open question. Our latest study shows that epsins and Dab2 competitively interact with VEGFR2. Furthermore, a synthetic UIM peptide inhibitor interferes with epsin-VEGFR2 association, heightens VEGF signaling and impedes tumor growth. Conversely, a synthetic peptide derived from Dab2 phospho-tyrosine binding (PTB) domain disrupts Dab2-VEGFR2 binding, reduces VEGF signaling and inhibits retinal angiogenesis. Therefore, we hypothesize that epsins and Dab2 differentially modulate VEGF signaling by competitively binding VEGFR2, and that targeting epsins and Dab2 may offer therapeutic potential in pathological angiogenesis. The roles of epsins and Dab2 in pathological angiogenesis and the molecular mechanisms underlying their differential regulation of VEGF signaling will be characterized using both in vitr and in vivo model systems.
In Aim 1, we will utilize multifactorial approaches to investigate molecular mechanisms by which epsin UIM specifically interacts with VEGFR2 to control VEGF signaling and angiogenic responses.
In Aim 2, we will employ biochemical characterization, dynamic imaging and immunofluorescence to determine how epsins and Dab2 differentially regulate VEGF signaling. These studies mechanistically link the differential regulations of VEGF signaling and function of epsins and Dab2.
In Aim 3, we will determine whether targeting epsins and Dab2 disrupts tumor angiogenesis and inhibits neovascular proliferative retinopathy. These studies will advance understanding of new pathways and new targets that differentially modulate VEGF signaling and may lead to new therapies targeting the pathological angiogenesis associated with cancer and diabetes.

Public Health Relevance

Pathological angiogenesis ensures tumor development, progression, and spread to other parts of body, which is the most common cause of death in the United States. Pathological angiogenesis also plays a leading role in the pathogenesis of diabetic retinopathy, which is the most common microvascular complication of diabetes and one of the major causes of blindness worldwide. In current application, we will define how a novel signaling adaptor protein, epsin and Dab2, another prominent endocytic sorting protein, control the development of pathological angiogenesis by regulating VEGF signaling. The findings will provide useful information on developing key reagents to advance the epsin- or Dab2-based targeting strategy for therapeutic intervention of pathological angiogenesis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL093242-09
Application #
9087313
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Gao, Yunling
Project Start
2008-07-01
Project End
2018-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
9
Fiscal Year
2017
Total Cost
$442,500
Indirect Cost
$192,500
Name
Boston Children's Hospital
Department
Type
Independent Hospitals
DUNS #
076593722
City
Boston
State
MA
Country
United States
Zip Code
02115
Dong, Yunzhou; Fernandes, Conrad; Liu, Yanjun et al. (2017) Role of endoplasmic reticulum stress signalling in diabetic endothelial dysfunction and atherosclerosis. Diab Vasc Dis Res 14:14-23
Dong, Yunzhou; Cai, Xue; Wu, Yong et al. (2017) Insights from Genetic Model Systems of Retinal Degeneration: Role of Epsins in Retinal Angiogenesis and VEGFR2 Signaling. J Nat Sci 3:
Song, Kai; Fu, Jianxin; Song, Jianhua et al. (2017) Loss of mucin-type O-glycans impairs the integrity of the glomerular filtration barrier in the mouse kidney. J Biol Chem 292:16491-16497
Song, Kai; Wu, Hao; Rahman, H N Ashiqur et al. (2017) Endothelial epsins as regulators and potential therapeutic targets of tumor angiogenesis. Cell Mol Life Sci 74:393-398
Bergstrom, Kirk; Liu, Xiaowei; Zhao, Yiming et al. (2016) Defective Intestinal Mucin-Type O-Glycosylation Causes Spontaneous Colitis-Associated Cancer in Mice. Gastroenterology 151:152-164.e11
Rahman, H N Ashiqur; Wu, Hao; Dong, Yunzhou et al. (2016) Selective Targeting of a Novel Epsin-VEGFR2 Interaction Promotes VEGF-Mediated Angiogenesis. Circ Res 118:957-969
Dong, Yunzhou; Wu, Hao; Rahman, H N Ashiqur et al. (2015) Motif mimetic of epsin perturbs tumor growth and metastasis. J Clin Invest 125:4349-64
Song, Kai; Herzog, Brett H; Fu, Jianxin et al. (2015) Loss of Core 1-derived O-Glycans Decreases Breast Cancer Development in Mice. J Biol Chem 290:20159-66
Chang, Baojun; Tessneer, Kandice L; McManus, John et al. (2015) Epsin is required for Dishevelled stability and Wnt signalling activation in colon cancer development. Nat Commun 6:6380
Liu, Xiaolei; Pasula, Satish; Song, Hoogeun et al. (2014) Temporal and spatial regulation of epsin abundance and VEGFR3 signaling are required for lymphatic valve formation and function. Sci Signal 7:ra97

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