Hong Chen, Ph.D.
Cardiovascular Biology Research Program
Adjunct Assistant Professor, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center
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.
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
2013 Winner of Irvine H. Page Young Investigator Research Award, Arteriosclerosis, Thrombosis and Vascular Biology Scientific Sessions, Orlando, FL, May 2013
2014 Merrick Award for Outstanding Research
Ad hoc Reviewer: Cell, Science, Nature Cell Biology, PNAS, EMBO J, EMBO Report, J Cell Biol, Developmental Cell, J Cell Sci, J Neuroscience, J Biol Chem, Oncogene, Blood, ATVB, Angiogenesis, J Clin Dermatol, J Mol Cell Biol, and J Clin Investig.
Ad hoc Grant Reviewer, National Science Foundation
Ad hoc Reviewer for The Medical Research Council, United Kingdom
Member of the Review Panel for AHA "Vascular Wall Biology Study Section III"
Ad hoc Reviewer for NIH "Vascular Cell Molecular Biology Study Section"
Ad hoc Reviewer for NIH "Atherosclerosis and Inflammation in Cardiovascular System Study Section"
American Heart Association
American Society for Cell Biology
American Association for the Advancement of Science
North American Vascular Biology Organization (NAVBO) member
American Association Cancer Research (AACR) member
Joined OMRF Scientific Staff in 2008.
The epsins are a protein family of growing importance in many normal and diseased processes. Mammals express three epsins, which are encoded by three different genes (Epn1, Epn2 and Epn3). Epsin 1 and 2 are expressed in all tissues and have redundant functions,while epsin 3 has a highly restricted tissue distribution. The redundancy of epsins 1 and 2 is exemplified by the normal life span of epsin 1 or 2 single knockout mice (KO) but embryonic lethality in epsins 1 and 2 double KO mice (DKO). Although epsins are universally expressed, they are not essential for housekeeping forms of clathrin-mediated endocytosis, including transferrin and EGF receptor endocytosis, but play a selective role in the endocytosis of specific cell surface ubiquitinated cargos. These cargos are recruited to clathrin-coated pits via ubiquitin-interacting motifs (UIM) on the epsins. Despite a well-defined role in vitro, the function of epsins in vivo, especially in adults are poorly understood. Current projects include but not limit to the following:
1) Vascular remodeling and angiogenesis.
To investigate the role of epsins in the adult vascular system, we generated mouse models that selectively lack epsins in endothelial cells (ECs). These mice exhibited no abnormal phenotypes under normal conditions, suggesting that lack of endothelial epsins 1 and 2 does not affect normal blood vessels. However, adult mice lacking endothelial epsins 1 and 2 exhibited highly disorganized tumor vasculature, significantly increased vascular permeability, and markedly retarded tumor growth. Mechanistically, we show that VEGF promotes binding of epsin to ubiquitinated VEGF receptor 2 (VEGFR2). Loss of epsins 1 and 2 specifically impairs endocytosis and degradation of VEGFR2, which results in excessive VEGF signaling that compromises tumor vascular function by exacerbating non-productive leaky angiogenesis. This suggests that tumor vasculature requires a balance in VEGF signaling to provide sufficient productive angiogenesis for tumor development, and that endothelial epsins 1 and 2 negatively regulate the output of VEGF signaling. Thus, promoting excessive VEGF signaling within tumors via a block of epsin function, may represent a strategy to prevent normal angiogenesis in cancer patients who are resistant to anti-VEGF therapies.
2) Lymphatic development.
The lymphatics are fundamental for collecting and returning extravasated fluid from tissues to blood circulation. The formation of functional lymphatic vessels requires the development of functional lymphatic valves (LVs). Proper LV development requires downregulation of VEGFR3 signaling but the mechanisms for downregulating VEGFR3 signaling during LV development remain elusive. Mice with lymphatic endothelial cell-specific deficiency of epsins (LEC-DKO) exhibit aberrant LV and abnormally enlarged lymphatics with decreased lymph drainage. This is due to increased VEGFR3 levels in collecting lymphatics, consistent with the idea that enhanced VEGFR3 signaling due to loss of epsins contributes to the development of abnormal, deficient LV. Our findings demonstrate an unrecognized critical role for epsins in regulating LV development and lymphatic function by fine tuning VEGFR3 signaling.
3) Vascular inflammation and atherogenesis.
The arterial inflammatory responses initiated by the oxidation of LDL trapped in the subendothelium are a key process that drives the initiation, progression, and even rupture of atherosclerotic plaques. To examine the role of endothelial epsins in atherogenesis, we engineered mice with constitutive deletion of epsins in EC (EC-DKO). Strikingly, these mice are viable but display markedly attenuated atherogenesis on an ApoE null background in response to hypercholesterolemia. Oil red O staining revealed that ApoE-/- mice with endothelial deletion of epsins had a significant reduction in atherosclerotic lesion area in aortic root and macrophage infiltration compared to ApoE-/- mice after being fed a western diet. Current effort focuses on uncovering how epsins control atherogenesis by potentiating inflammation in endothelium and seeking a potential novel strategy to perturb atherogenesis.
Inventor: Dr. Chen and Dr. Dong
Title: Ubiquitin interacting Peptides as Cancer Therapeutics
Date Filed: 1/31/2012
United States Patent Application: 20120197059
Messa M, Fernandez-Busnadiego R, Sun EW, Chen H, Czapla H, Wrasman K, Wu Y, Ko G, Ross T, Wendland B, De Camilli P. Epsin deficiency impairs endocytosis by stalling the actin-dependent invagination of endocytic clathrin-coated pits. ELife 3:e03311, 2014. [Abstract]
Chen H, Griffin C, Xia L, Srinivasan RS. Molecular and cellular mechanisms of lymphatic vascular maturation. Microvasc Res 2014. [Abstract] EPub
Tessneer KL, Pasula S, Cai X, Dong Y, McManus J, Liu X, Yu L, Hahn S, Chang B, Chen Y, Griffin C, Xia L, Adams RH, Chen H. Genetic Reduction of Vascular Endothelial Growth Factor Receptor 2 Rescues Aberrant Angiogenesis Caused by Epsin Deficiency. Arterioscler Thromb Vasc Biol 34:331-337, 2014. [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]
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]
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
Yunzhou Dong, Ph.D.
Research Assistant Member
Baojun Chang, M.D., Ph.D.
Associate Staff Scientist
Hao Wu, Ph.D.
Assistant Staff Scientist
Hoogeun Song, Ph.D.
Senior Postdoctoral Fellow
Xiaofeng Cai, M.D., Ph.D.
Satish Pasula, Ph.D.
Kandice Tessneer, Ph.D.
Senior Research Technician
Administrative Assistant III