The candidate's long term goals are to study the role of the effector immune system in regulating ocular angiogenesis in the sub-retinal space. Ocular involvement in age-related macular degeneration (AMD) often leads to significant visual impairment as a result of neovascularization in the sub-retinal space with subsequent damage to the underlying choriocapillaris and overlying retinal photoreceptors. AMD is the leading cause of blindness among the population over 65 years of age in North America, Europe and Australia. The morbidity from AMD is expected to rise exponentially as the population ages. Current treatments are at best palliative in nature. Age-related changes in the ocular tissues including the retinal pigment epithelium (RPE) and Bruch's membrane perturb the delicate oxygen balance within the ocular micromilieu and might affect immune effector mechanisms within the retina and choroid. Normal RPE plays a crucial role in maintaining a viable and healthy outer retina. It also inhibits pro-angiogenic stimuli and is critical in maintaining a normal retinochoroidal interface. A combination of RPE dysfunction and a dysregulated immune effector system create a potentially pro-angiogenic environment in the sub-retinal space. The immune system might play a critical role in altering the native characteristics of the RPE and choroidal endothelial cells. The sub-retinal space then becomes a favorable environment for the development of choroidal neovascularization (CNV). It has indeed been shown in animal models that immune effector cells are critical for the initiation and sustenance of CNV. An understanding of the pathophysiology and signaling cascades that promote ocular angiogenesis and the influence of the immune system on these processes has broad implications for the understanding of ophthalmic diseases such as AMD, diabetic retinopathy, retinopathy of prematurity and ocular melanomas which affect diverse age groups and wherein angiogenesis is critical to the disease processes. The candidate proposes to study the immunology and molecular mechanisms of ocular angiogenesis in the sponsor's laboratory. During the duration of the proposal, he will a) study the role of the immune system and associated cytokine polarization in ocular angiogenesis, b) seek to identify and characterize host ocular tissue factors modulated by effector cytokines in a murine laser-induced model of CNV, and c) define the signaling pathways that promote vascular endothelial cell proliferation in the sub-retinal space during the development of CNV. ? ?
