Introduction: Age-related macular degeneration (AMD) is the leading cause of elderly blindness in the U.S. Absence of good animal models has limited mechanistic understanding and thwarted development of therapies. We observed that mice genetically deficient either in the macrophage chemokine CCL2 or its cognate receptor CCR2 develop the pathological hallmarks of AMD in an age-dependent fashion. Preliminary Data: (1) CCL2-/- and CCR2-/- mice develop lipofuscin, drusen, geographic atrophy, and choroidal neovascularization (CNV) as they age. (2) Complement C5 and IgG are deposited in the retinal pigmented epithelium (RPE) and choroid of both knockout strains as they age, as in patients with AMD. (3) These findings are not present in age-matched wild-type mice. (4) Macrophages infiltrate into the choroid of aged wild-type mice but not knockouts in large numbers. (5) C5a and IgG upregulate RPE secretion of CCL2. (6) C5a and IgG upregulate RPE and choroidal endothelial cell secretion of vascular endothelial growth factor (VEGF), consistent with CNV development. (7) Macrophages are immobilized by and adhere to C5a & IgG. Hypotheses: (1) The accumulation of drusen and lipofuscin associated with senescence in CCL2-/- or CCR2- /- mice is due to impaired clearance by scavenger macrophages, whose recruitment is impaired in the absence of CCL2 or its receptor CCR2, and ultimately leads to geographic atrophy and CNV. (2) Rescue of CCL2 or CCR2 function can prevent or regress AMD-like pathology in knockout mice. Specific Aims: (1) To quantify the development of AMD-like features in CCL2-/- or CCR2-/- mice by ophthalmoscopy, angiography, and histopathology, compared to age-matched wild-type mice. (2) To demonstrate that protein deposits found in the RPE and choroid of senescent CCL2-/- or CCR2-/- mice stimulate CCL2 and VEGF production, and that macrophages adhere to and degrade these protein deposits. (3) To demonstrate that rescue of CCL2 or CCR2 function inhibits or regresses AMD-like pathology in elderly CCL2-/- or CCR2-/- mice. Significance: These studies will provide mechanistic insights into and more effective treatments for AMD.