Proliferative retinopathies (PRs) are a classification of diseases that include sickle cell retinopathy, diabetic retinopathy, branch vein occlusion retinopathy, and retinopathy of prematurity. These diseases all are characterized by the loss of normal blood vessels in the retina and subsequent uncontrolled growth of abnormal blood vessels in the vitreous of the eye. As in humans, retinal ischemia in mice induces growth of abnormal vessels in the vitreous. In contrast to humans, mice are only transiently affected by the growth of abnormal blood vessels in the vitreous. Within a short period, normal blood vessels will re-grow within the mouse retina and the abnormal vessels in the vitreous will spontaneously resolve. The regrowth of normal retinal vessels provide mice with an endogenous mechanism for long-term protection from proliferative retinopathy. We hypothesize that the rodent retina is competent to promote retinal vascular regrowth through the expression of genes that are essential regulators and effectors of blood vessel growth and stability. Our goal is to identify the molecular regulators and effectors of vascular growth in the mouse retina. We have previously demonstrated that transgenic expression of either activated transforming growth factor 131(TGF-131) or leukemia inhibitory factor (LIF) in the lens alters the environment within the retina so that it is no longer competent for vascular development. Our strategy is to identify the genes that are expressed in wild type retinas which can promote vascular development, but that are not expressed in retinas which have lost the ability to support vascular development. In the current proposal, we will use transgenic mice in which we can induce the expression of TGF-131 (aim 1), or LIF (aim 2) in retinal photoreceptors, so that we can turn off retinal competence for vascular development at ages corresponding to the beginning, to the middle, and to completion of normal retinal vascular development (aims 1 and 2). With these mice, we will test the hypothesis that cytokines reduce growth of vascular endothelial cells or increase vascular degeneration. We will also test the hypothesis that cytokines down-regulate the expression of specific genes that are necessary for retinal vascularization (aim 3). This will allow us to identify genes that are regulators and effectors of retinal vascular development in mice.
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