CCR3 biology and imaging applied to Chorodial Neovascularization in Age-Related Macular Degeneration

Age related macular degeneration (AMD) is the leading cause of blindness over the age of 55 years. Most blindness in AMD results from invasion of the retina by choroidal neovascularization (CNV). There is abundant evidence that inflammatory and immunologic mediators play a 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 CNV in an animal model (Takeda, Baffi, Nature 2009). We have showed that CCR3, previously assigned as an eosinophillmast cell chemokine receptor involved in allergic responses, was expressed by human choroidal endothelial cells in CNV tissue specimens excised from patients with active, neovascular AMD. Pharmacological or genetic targeting of CCR3 or its ligands inhibited injury-induced CNV in mice. Furthermore, targeting CCR3 or its eotaxin ligands inhibited angiogenesis in vitro and in vivo, and was both superior to and safer than VEGF-A blockade. Concomitantly, in vivo imaging with CCR3-targeting quantum dots located spontaneous CNV invisible to standard fluorescein angiography in mice before retinal invasion. These findings establish CCR3 as an ideal diagnostic and therapeutic target for neovascular AMD. This proposal seeks to further understand the role and impact of resident versus circulating bone marrow-derived cell contribution to CCR3 function in CNV using multiple molecular, biological, and genetic approaches, and to create a novel CCR3 bioimaging strategy to visualize the earliest stages of neovascular AMD. The potential impact of this proposal is very high as it wifi define the further define the function of the CCR3/eotaxin axis in the pathogenesis of AMD, and lead to the development of novel CCR3- targeting diagnostic and therapeutic strategies that can be used in the clinic to detect the subclinical stages of neovascular AMID, thus preventing progression to the fulminant neovascular stage.