CCR3 as an Early Detection Target in Age Related Macular Degeneration

Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly and affects 30-50 million people worldwide. Most blindness in AMD results from invasion of the retina by choroidal neovascularization (CNY). There is abundant evidence that inflammatory and immunologic mediators playa significant role in the development of AMD and its progression to choroidal neovascularization. but the exact molecular basis of immune regulated angiogenesis is still unknown. Recently I, along with other members of the Macular Degeneration Research Group at the University of Kentucky, identified the chemokine receptor CCR3 as a unique molecular signature of CNY in humans with AMD (Takeda, Baffi et al., Nature 2009). We have showed that CCR3. previously assigned as an eosinophil/mast cell chemokine receptor involved in allergic responses. was expressed by human choroidal endothelial cells in CNY tissue specimens excised from patients with active. neovascular AMD. Phannacological or genetic targeting of CCR3 or its ligands inhibited injury-induced CNY in mice. Furthennore, targeting CCR3 or its eotaxin ligands inhibited angiogenesis in vitro and in vivo. and was both superior to and safer than YEGF-A blockade. Concomitantly, in vivo imaging with CCR3-targeting quantum dots located spontaneous CNY. invisible to standard fluorescein angiography, in mice before retinal invasion. These findings establish CCR3 as an ideal diagnostic and therapeutic target for neovascular AMD. We hypothesize that CCR3 can be a gateway to early detection and intervention in this devastating blinding disease. This proposal seeks to further understand how the specificity of CCR3 to neovascular AMD is established. and develop refined molecular imaging tools to visualize the earliest stages of choroidal neovascularization through the following two Specific Aims: