Haibo Wang, MD, PhD, has a strong interest in retinal diseases and is particularly interested in the signaling pathways involved in retinal endothelial and epithelial cell motility, migration, and junctional properties. Before joining the laboratory of Mary Elizabeth Hartnett, MD, Dr. Wang received four years of training in the field of metabolic diseases, focusing on the G-protein coupled receptor signaling pathway in regulating energy metabolism and accruing rich experiences in molecular biology, cell biology, and signaling cascades.
With Dr. Hartnett, Dr. Wang has addressed questions regarding both physiologic and pathologic angiogenesis, specifically of signaling pathways involving VEGF/VEGF receptor, erythropoietin (EPO)/EPO receptor, Rac1, CCR3 and Rap1 in regulating pathologic angiogenesis in neovascular age-related macular degeneration (AMD). As co-investigator, Dr. Wang performs in-vitro experiments assessing cell signaling (eg., VEGF, Rac1, CCR3 and Rap1), protein interactions, and cell transduction with adenoviral constructs and with IQGAP1 binding domain mutant constructs. Dr. Wang is responsible for siRNA/shRNA techniques, those involving in vitro mechanisms of IQGAP1 and Thy-1/IQGAP1 interactions. She also performs and oversees analyses of Western blots, PCR, and ELISAs on tissue and cell samples that are done by others in the laboratory.
Dr. Wang works with the laboratory team to address research frameworks; she generates hypotheses and designs experiments to test these as results are obtained. She also helps train post-doctoral students and technicians and in writing manuscripts.
Dr. Wang’s contributions to science include:
1. Studies in Neovascular Age-related Macular Degeneration
Neovascular age related macular degeneration (AMD) is the leading cause of legal blindness in people older than 60 years of age. Intravitreal injection of anti-VEGF agents has become the standard of care for choroidal neovascularization (CNV) in neovascular AMD; however, reports indicate about 40 percent of patients with neovascular AMD respond to anti-VEGF treatment.
One reason may be that treatment is provided too late when CNV is already present. To address this possibility, the Hartnett laboratory focuses on understanding early steps in the pathophysiology in neovascular AMD in order to prevent vision loss. Activation and migration of choroidal endothelial cells (CECs) are early steps in the development of CNV. Activated CECs migrate through Bruch’s membrane toward the retinal pigment epithelium (RPE) and also transmigrate the RPE with reduced barrier function into the sensory retina. At either location, activated CECs can proliferate to form CNV. Severe vision loss occurs when CNV develops in the sensory retina.
While working in Dr. Hartnett’s laboratory and addressing her overall framework on neovascular AMD, Dr. Hartnett and Dr. Wang found 1) age related upregulation of CCR3 and interactions of CCR3 with VEGFR2 in choroidal endothelial cells; 2) that activation of Rap1 GTPase can improve the integrity of the barrier of the retina pigment epithelium (RPE) and reduce vision loss from choroidal neovascularization (CNV) via a mechanism involving NADPH oxidase mediated ROS generation; and 3) that activation of Rap1a inhibits activated Rac1-mediated CEC migration induced by inflammatory cytokine, TNF alpha.
2. Studies in Retinopathy of Prematurity
Retinopathy of Prematurity (ROP) is a leading cause of childhood blindness worldwide. The Hartnett laboratory studies two important sequential phases of ROP: delayed-physiologic retinal vascular development (delayed-PRVD) in phase I, which can lead to blindness from vasoproliferative, intravitreal neovascularization (IVNV) in phase II.
Standard of care for ROP including laser treatment and anti-angiogenic strategies, such as inhibitors of vascular endothelial growth factor (VEGF), intends to reduce IVNV, but is destructive or interferes with physiologic retinal vascular development. Thus, better treatments are needed. The Hartnett laboratory long-term goal is to develop treatments to inhibit IVNV but not interfere with physiologic retinal vascular development and that are safe for developing preterm infants.
In addressing Dr. Hartnett’s overall research framework, Dr. Wang and Dr. Hartnett identified potential targets to safely reduce IVNV and not interfere with physiologic retinal vascular development. First, in a rat model of human ROP, STAT3 delayed physiologic retinal vascular development or exacerbated IVNV based on the cell type in which the STAT3 was activated. They found that endothelial cell and Müller cell STAT3 had different signaling effects on physiologic retinal vascular development and IVNV.
Through knowledge of signaling pathways, future treatments can be developed by targeting EC specific STAT3 or NOX4 or Müller cell specific VEGF.
1. Wang H, Geisen P, Wittchen ES, King B, Burridge K, D'Amore PA, Hartnett ME. (2011). The role of RPE cell-associated VEGF in choroidal endothelial cell transmigration across the RPE. Invest Ophthalmol Vis Sci, 52(1), 570-8. PMC3053298
2. Haibo Wang, Grace Byfield, Yanchao Jiang, George Wesley Smith, Manabu McCloskey, M. Elizabeth Hartnett. (2012). VEGF-mediated STAT3 activation inhibits retinal vascularization by downregulating erythropoietin expression. American Journal of Pathology, 180(3):1243-53. PMC3349887
3. Wang H, Smith GW, Yang Z, Jiang Y, McCloskey M, Greenberg K, Geisen P, Culp WD, Flannery J, Kafri T, Hammond S, Hartnett ME. (2013). Short hairpin RNA mediated knockdown of VEGFA in Müller cells reduces intravitreal neovascularization in a rat model of ROP. Am Journal of Path, 183(3):964-74. PMC3763762
4. Wang H, Jiang Y, Shi D, Quilliam LA, Chrzanowska-Wodnicka M, Wittchen ES, Li DY, Hartnett ME. (2014). Activation of Rap1 inhibits NADPH oxidase-dependent ROS generation in retinal pigment epithelium and reduces choroidal neovascularization. FASEB J., 28(1):265-74. PMC3868836
5. Haibo Wang, Erika S. Wittchen, Yanchao Jiang, Balamurali Ambati, Hans E. Grossniklaus, M. Elizabeth Hartnett. (2011). Upregulation of CCR3 by age-related stresses promotes choroidal endothelial cell migration via VEGF-dependent and independent signaling. Invest Ophthalmol Vis Sci. 52(11):8271-7 PMC3208059
6. Wang H, Jiang Y, Shi D, Quilliam LA, Chrzanowska-Wodnicka M, Wittchen ES, Li DY, Hartnett ME. (2014). Activation of Rap1 inhibits NADPH oxidase-dependent ROS generation in retinal pigment epithelium and reduces choroidal neovascularization. FASEB J. 28(1):265-74 PMC3868836
7. Wang H, Fotheringham L, Wittchen ES, Hartnett ME. (2015). Rap1 GTPase Inhibits Tumor Necrosis Factor-α-Induced Choroidal Endothelial Migration via NADPH Oxidase- and NF-κB-Dependent Activation of Rac1. American Journal of Pathology, 185(12):3316-25 PMID: 26476350
8. Haibo Wang, Xiaokun Han, Erika S. Wittchen, M. Elizabeth Hartnett. (2016).TNF-α mediates choroidal neovascularization by upregulating VEGF expression in RPE through ROS-dependent β-catenin activation. Molecular Vision 22,116-128 PMID:269003287
9. Haibo Wang, Yuan Zhang, Einav Shnaidman, Alexander V. Medvedev, Naresh Kumar, Kiefer W. Daniel, Jacques Robidoux, Micheal Czech, David J Mangelsdorf, Sheila Collins. (2008). LXR is a transcriptional repressor of uncoupling protein-1 and the brown fat phenotype. Mol. Cell Biol. 28(7):2187-200 PMC2268430
10. Kumar N, Liu D, Wang H, Robidoux J, Collins S. (2008). Orphan nuclear receptor NOR-1 enhances cAMP-dependent uncoupling protein-1 gene transcription. Molecular Endocrinology, 22(5):1057-641 PMC2366189
11. Naresh Kumar, Haibo Wang, Dianxin Liu, Sheila Collins. (2009). Liver X receptor is a regulator of orphan nuclear receptor NOR-1 gene transcription in adipocytes. International Journal of Obesity, 33(5):519-24 (equal contribution with the first author) PMID: 19238156
12. Hao Q, Hansen JB, Petersen RK, Hallenborg P, Jørgensen C, Cinti S, Larsen PJ, Steffensen KR, Wang H, Collins S, Wang J, Gustafsson JA, Madsen L, Kristiansen K. (2010). ADD1/SREBP1c activates the PGC1-alpha promoter in brown adipocytes. Biochim Biophys Acta. 1801(4):421-429 PMID: 19962449