The role of Tbx3 in retinal angiogenesis and eye disease - Patients with neovascular disease, including Retinopathy of Prematurity and Familial Exudative Vitreoretinopathy (FEVR), develop insufficiently vascularized, or hypovascular, retinas. We have observed a similar hypovascular phenotype in the Tbx3 conditional knockout retina. Our long-term goal is to understand how retinal neurons and vascular cells form the neurovascular unit. The objective of this proposal is to determine the role Tbx3 plays in retinal angiogenesis as a way to uncover new molecular mechanisms driving retinal vascular disease. In our model, TBX3 is required during three events that are essential for retinal angiogenesis, when 1) retinal ganglion cells become metabolically active, causing retinal astrocytes to proliferate; 2) the embryonic hyaloid vasculature regresses in response to increases in dopamine levels; and 3) astrocytes migrate into the retina to form the astrocytic lattice. Our central hypothesis is that TBX3 regulates signals that affect retinal angiogenesis via its regulation in three separate cell types: first, in dorsal retinal ganglion cells, next, in dopaminergic amacrine cells, and finally, in astrocytes. The rationale underpinning this hypothesis is that key genetic networks controlling neurogenesis and angiogenesis are shared and thereby coordinate neurovascular coupling. We will test the central hypothesis by determining the TBX3-regulated molecular mechanisms that affect angiogenesis in 1) dorsal retinal ganglion cells via Sonic Hedgehog signaling, 2) dopaminergic amacrine cells via regulation of tyrosine hydroxylase, and 3) retinal astrocytes via control of migration. Each of these aims will be pursued using a combination of large-scale transcriptomic studies coupled with genetic manipulation and molecular analysis, which are standard technologies in our lab. Our studies are significant because they will fill a major gap in knowledge about vascular formation and identify new molecular pathways activated during angiogenesis. The expected outcome of this work is that it will add to our fundamental knowledge about retinal angiogenesis. Moreover, these studies will produce a database of dorsal-specific factors that will provide an understanding of the fundamental, cellularly distinct, differences in this region of the retina. In addition, this research fits in well with the NEI’s goal of ‘study[ing]…genetic factors that underlie structure, function, and the biology of retinal diseases.’ Our results will have a positive, immediate impact because they will provide a better understanding of retinal angiogenesis, and long-term impact because we expect our research will identify novel targets for better therapies of vascular disease.
