The Manton Center for Orphan Disease Research
Jing Chen, PhD
Dr. Chen received her PhD in biomedical engineering from Boston University for her studies in visual neuroscience. She completed her research fellowship in Ophthalmology at Boston Children's Hospital.
Dr. Chen's current research studies three related blinding orphan eye disease: familiar exudative vitreoretinopathy (FEVR), Norrie disease and Coats' disease, all of which have lack of blood vessel growth in the retina. This poor vascularization causes low tissue oxygen which then stimulates abnormal and sight-threatening blood vessel proliferation. The goal of Dr. Chen's work is to understand the cellular and molecular pathways that regulate retinal blood vessel growth in these diseases, and identify ways to modulate these pathways to prevent and treat the diseases.
Dr. Chen has received several awards including a Juvenile Diabetes Research Foundation Postdoctoral Fellowship, a Knights Templar Eye Foundation Pediatric Ophthalmology Research Award, and a Junior Faculty Career Development Award from The Manton Center for Orphan Disease Research at Boston Children's Hospital for her work on "Regulation of Retinal Angiogenesis by Wnt Signaling."
Regulation of Retinal Angiogenesis by Wnt Signaling
A common fundamental problem in three related blinding orphan eye diseases, familial exudative vitreoretinopathy (FEVR), Norrie disease and Coats' disease, is a lack of blood vessel growth in the retina. This poor vascularization causes low tissue oxygen in the retina which then stimulates subsequent abnormal and sight-threatening vessel proliferation. Current ablation surgery is only partially effective in suppressing pathologic vessel growth to prevent vision loss in these diseases. A more refined approach promoting normal vascularization rather than inhibiting all vessels depends on a better understanding of the inter-related pathways involved in these diseases which share a common phenotype. Norrie disease, FEVR, and Coats' disease all have in common abnormalities of Wnt signaling pathways, a pathway fundamentally important for embryonic development. Since mutations involve Wnt receptor Frizzled4, co-receptor LRP-5 and Wnt ligand Norrin has been associated with all of these orphan diseases in human, studies in Wnt signaling is likely to lead us to the mechanism of poor retinal vascular growth and design of potential therapies to selectively promote normal vessel growth and inhibit pathological neovessels.
Preliminary results show that Wnt signaling is specific for neovessel sprouting in the retina. We will further study the role of Wnt signaling in retinal blood vessel growth by assessing vessel formation in mice with gain or loss of function, or reporter activity in Wnt signaling. We will determine the integration of Wnt signaling with known angiogenic pathways to influence neovessel formation in retinal vessels isolated from transgenic mice with loss of Wnt signaling. We will examine the source of specific secreted Wnt ligands in retinal neurons and inflammatory cells and determine their effects on mediating vascular endothelial cell sprouting. Finally we will modulate the Wnt pathway with specific activators and inhibitors to assess their role in preventing vessel loss and pathologic vessel growth in mouse models of retinopathy. Successful completion of the proposed research is likely to show how we may modulate Wnt pathway to treat blinding rare eye diseases such as FEVR, Norrie's disease, Coats' disease, as well as retinopathy of prematurity and persistent fetal vasculature. This work is likely to also lead to discovery of new surrogate markers of disease risks for diagnosis and early prevention of these diseases.