Research & Publications
I have focused on translational research from the very beginning of my postgraduate study. To discover the molecular mechanisms and facilitate new therapeutic strategies for vascular diseases, I have worked on angiogenesis and lymphangiogenesis, predominantly to investigate the role of CCM3, Trx2, SENP1 and AIP1 genes in animal models and in vitro for vascular biology, cell biology and signaling, as well as potential therapeutic targets which would provide promising treatment for vascular diseases such as cerebral cavernous malformation, diabetic retinopathy and cardiomyopathy. Specifically, I have 1) defined novel function of AIP1 in regulating VEGFR3 signaling in angiogenesis and lymphangiogenesis (Arterioscler Thromb Vasc Biol, 2014); 2) elucidated critical function of mitochondrial redox protein Trx2 in cardiomyopathy in collaboration with Dr. Huang in the lab (Circulation, 2015), and found Trx2 modulates vessel sprouting and maturation in angiogenesis (ongoing work); 3) demonstrated that SENP1 functions as an endogenous activator in VEGFR2 signalling by regulating VEGFR2 trafficking from the Golgi to endothelial cell surface which pathway plays a critical role in diabetes-associated angiogenesis (Nat Commun, 2018); 4) established inducible endothelial-specific CCM3 mouse model for human cerebral cavernous malformation (CCM) disease and have intriguingly found that blockade of exocytosis or inhibition of Angpt2-TIE2 signaling completely blunts CCM lesion formation in the mouse model (Nat Med, 2016; Nat Commun, 2021).
News and Views at: http://www.nature.com/nm/journal/v22/n9/full/nm.4178.html
Extensive Research Description
1. Cerebral cavernous malformations:Cerebral cavernous malformations (CCMs) are common vascular malformations with a prevalence of 0.4-0.8% that affect the vasculature of central nervous system in the human population where they result in increased risk for stroke, seizures and focal neurological deficits. My research aims to address the following fundamental questions: Why are CCM lesions primarily confined to brain vasculature despite CCM proteins are ubiquitously expressed in all tissues? Which is the major cell type in which CCM loss initiates CCM lesion formation? And what is the critical signaling in endothelial cells and pericytes that contributes to CCM disease? I expand my current study of CCM3 to explore the hypothesis that loss of CCM3 in endothelial cells (EC) and pericytes (PC) alters signaling critical for EC-PC interactions, contributing to vascular disassembly and capillary dilation within the neurovascular unit, leading to CCM (Nat Med, 2016; Arterioscler Thromb Vasc Biol, 2020; Nat Commun, 2021). I will use the complementary approaches of genetic, cell biological and imaging analyses to define augmented membrane protein targeting in a specialized cell type within neurovascular unit as the causes of CCM pathology, and define new and more effective therapies for this potentially debilitating neurological disorder.
2. Elucidate critical function of mitochondrial redox protein in vascular diseases:Thioredoxin 2 (Trx2) is a key mitochondrial protein that regulates cellular redox and survival by suppressing mitochondrial reactive oxygen species generation. Because mice with a constitutive deletion of Trx2 in endothelial cell were lethal, I generated endothelial-specific tamoxifen-inducible Trx2 loss-of-function mice, and am investigating the role of Trx2 in retina angiogenesis and retina diseases.
Positions available (for Students, Postdocs and Visiting Scholars): We are open to highly motivated postgraduate students and postgraduates including visiting scholars who has MD degree, PhD degree/candidate, both MD and PhD degree/candidate, to work on exciting on-going directions, especially vascular biology and malformations, vascular diseases (CCM, AVM, Eye diseases and Lymphatic diseases) and translational perspectives. We prefer someone who is experienced in both in vivo and in vitro study. Please contact me directly (email@example.com) with your updated CV if you are interested.
Arteriovenous Malformations; Blood Vessels; Blood-Brain Barrier; Cardiovascular Diseases; Endothelium
Public Health Interests