Blood vessels play an important part in healthy living, but they’re also integral to some diseases. For example, in cancer, an excess of vessels feeds tumors, helping them grow. The more we know about how vessels work – how they form and repair themselves – the greater the possibility that we can find ways to control their growth and development.

To learn about blood vessels at the cellular level, we look at a process called endocytosis, the way in which all cells interact with their environment. In normal endocytosis, cells behave as they should and perform their prescribed function, but abnormalities in the process can result in cardiovascular disease, diabetes, cancer and neurological disorders. Using a mouse model, we create conditions in which vessels begin to form to study the molecular mechanisms at work in the vascular system’s earliest stages.

In my lab, we investigate the role of “epsins,” a family of proteins that influence vascular growth factors, both in embryos and adults. These growth factors encourage cells to grow, multiply and form new vessels. Under normal circumstances, just the right number of vessels develops to maintain health. But when growth factors go awry, vessels can grow out of control, mimicking cancer or causing cardiovascular disorders.

If we can identify ways to control vessel-promoting factors, we may learn how to stabilize or decrease vessel growth in the body. In cancer, it could lead to “road blockers” for stopping blood flow to tumors without harming the rest of a person’s blood vessel system.

Education
B.S., Nankai University, China, 1991
M.S., Pennsylvania State University, PA, 1995
Ph.D., Yale University, New Haven, CT, 1999

Honors and Awards
1992 Honors Award for Academic Excellence, Nankai University, China
1995-1996 Kenneth and Mary Wang Foundation Fellowship, Yale University
1998 Predoctoral Travel Award, 38th American Society for Cell Biology meeting, San Francisco
1999 Distinguished Ph.D. Thesis Award, Yale University
2000 The John Sprangler Nicholas Prize for distinguished Ph.D., Yale University
2000-2004 Howard Hughes Medical Institute Postdoctoral Fellow
2004 First Prize, poster “Epsin mediates the endocytosis of ubiquitinated plasma membrane cargo proteins,”
Cell Biology Retreat, Yale University
2005-2006 Pilot Research Feasibility Award from Yale Diabetes Endocrinology Research Center, Yale University
2006 First Prize, poster “Genetic analysis of Epsin 1 and 2 reveals a redundant but essential role in Notch signaling in mice,” Cell Biology Retreat, Yale University
2008-2012 American Heart Association National SDG Award

Other Activities
Ad hoc reviewer: Cell, Science, Nature Cell Biology, PNAS, EMBOJ, J Cell Biol, Developmental Cell, J Cell Sci, J Neuroscience and J Biol Chem.
Ad hoc grant reviewer, National Science Foundation

Memberships
American Heart Association
American Society for Cell Biology
American Association for the Advancement of Science

Joined OMRF Scientific Staff in 2008.

Endocytosis is a fundamental mechanism used by cells to communicate with the environment. It is critical for antigen presentation, nutrient uptake, lipid membrane exchange and receptor internalization. Endocytosis of activated receptors can regulate many cellular events including signal transduction, and malfunctions in endocytosis can contribute to pathological conditions leading to a variety of illnesses. Among these are cardiovascular disease, diabetes, cancer and neurological disorders, highlighting its central role in maintaining cellular homeostasis.

We previously showed that epsins are a founding family of endocytic adaptor proteins required for internalization and degradation of ubiquitinated receptors. More recently, we showed that deletion of epsins 1 and 2 increases VEGF signaling in endothelial cells, and inhibits Notch signaling in developing embryos. Thus, the research in the lab centers on exploring how epsin-mediated endocytosis regulates receptor signaling in vitro and how this regulation controls physiological and pathological consequences in vivo. In particular, we are interested in studying the following three research areas:

The first research theme is to determine how epsin-mediated endocytosis of vascular endothelial growth factor receptors (VEGFR) affects VEGF signaling and modulates angiogenesis and lymphangiogenesis both physiologically and pathologically. We have generated mutant mice that lack epsin 1 and 2 globally or selectively in endothelial cells. We will utilize these mutant mice to determine the function of epsins in regulating both angiogenesis and lymphangiogenesis. We also seek to define the molecular mechanism underlying the regulation of VEGF signaling by epsin-mediated endocytosis of VEGF receptors.

Secondly, we are investigating how epsin-mediated endocytosis of Notch ligand, Dll4, activates Notch signaling and consequently regulates embryonic angiogenesis, including arterial-venous differentiation. We plan to use endothelial cell-specific, epsin double-knockout mice to assess Notch signaling defect and abnormal embryonic angiogenesis.

Our third research theme centers on probing the role of epsin in cancer by controlling tumor growth and metastasis via modulating tumor angiogenesis and lymphangiogenesis. Our ultimate goal is to identify new vascular targets for drugs that inhibit tumor growth and spreading. Furthermore, epsin mutant mouse models are ideally suited for investigating other receptors important for vascular development and remodeling. Examples include angiopoietins (Ang1 and Ang2) and their cognate receptors (Tie2 and Tie1) and platelet-derived growth factor β (PDGFβ) and its receptors. These studies will provide valuable information for the identification of novel factors and drug targets that treat a range of human diseases with a vascular component.

Recent Publications

Huang Q, Qin L, Dai S, Zhang H, Pasula S, Zhou H, Chen H, Min W. AIP1 Suppresses Atherosclerosis by Limiting Hyperlipidemia-Induced Inflammation and Vascular Endothelial Dysfunction. Arterioscler Thromb Vasc Biol 33:795-804, 2013. [Abstract]

* Pasula S, Cai X, Dong Y, Messa M, McManus J, Chang B, Liu X, Zhu H, Mansat RS, Yoon SJ, Hahn S, Keeling J, Saunders D, Ko G, Knight J, Newton G, Luscinskas F, Sun X, Towner R, Lupu F, Xia L, Cremona O, De Camilli, P, Min W, Chen H. Endothelial epsin deficiency decreases tumor growth by enhancing VEGF signaling. J Clin Invest 122:4424-4438, 2012. [Abstract]  Commentary: Klauber-Demore N. Are epsins a therapeutic target for tumor angiogenesis? J Clin Invest 122: 4341-3, 2012. [Abstract]

Ji W, Li Y, Wan T, Wang J, Zhang H, Chen H, Min W. Both internalization and AIP1 association are required for tumor necrosis factor receptor 2-mediated JNK signaling. Arterioscler Thromb Vasc Biol 32:2271-2279, 2012. [Abstract]

Selected Publications
Chen, H, Ko, G, Zatti, A, Di Giacomo, G, Liu, L, Raiteri, E, Perucco, E, Collesi, C, Min, W, Zeiss, C, De Camilli, P, Cremona, O. Embryonic arrest at midgestation and disruption of Notch signaling produced by the absence of both epsin 1 and epsin 2 in mice. Proc Natl Acad Sci USA 106:13838-13843; 2009.[Abstract]

Polo S, Sigismund S, Faretta M, Guidi M, Capua MR, Bossi G, Chen H, De CP, Di Fiore PP. A single motif responsible for ubiquitin recognition and monoubiquitination in endocytic proteins. Nature 416:451-455, 2002. [Abstract]

Chen H, Fre S, Slepnev VI, Capua MR, Takei K, Butler MH, Di Fiore PP, De CP. Epsin is an EH-domain-binding protein implicated in clathrin-mediated endocytosis. Nature 394:793-797, 1998. [Abstract]

Takei K, Haucke V, Slepnev V, Farsad K, Salazar M, Chen H, De CP. Generation of coated intermediates of clathrin-mediated endocytosis on protein-free liposomes. Cell 94:131-141, 1998. [Abstract]

Shupliakov O, Low P, Grabs D, Gad H, Chen H, David C, Takei K, De CP, Brodin L. Synaptic vesicle endocytosis impaired by disruption of dynamin-SH3 domain interactions. Science 276:259-263, 1997. [Abstract]

Chen H, Li B, Workman JL. A histone-binding protein, nucleoplasmin, stimulates transcription factor binding to nucleosomes and factor-induced nucleosome disassembly. EMBO J 13:380-390, 1994. [Abstract]

Cardiovascular Biology Research Program, MS 45
Oklahoma Medical Research Foundation
825 N.E. 13th Street
Oklahoma City, OK 73104

Phone: (405) 271-2750, 12755
Fax: (405) 271-3173
E-mail: Hong-Chen@omrf.org

Yunzhou Dong, Ph.D. 
Research Assistant Member

Baojun Chang, M.D., Ph.D. 
Associate Staff Scientist

Xiaofeng Cai, M.D., Ph.D.
Postdoctoral Fellow

Satish Pasula, Ph.D. 
Postdoctoral Fellow

Kandice Tessneer, Ph.D.
Postdoctoral Fellow

John McManus
Laboratory Manager

Scott Hahn
Research Assistant

Yiyuan Chen
Research Technician

Lili Yu
Research Technician

Xiaolei Liu
Affiliate

Natalie Fessler
Administrative Assistant III