Grants and Contracts Details
We recently reported in Nature Medicine that mice genetically deficient either in Ccl-2 (C-C chemokine ligand-2; also known as monocyte chemoattractant protein-I) or its cognate Ccr-2 receptor develop the pathological hallmarks of age-related macular degeneration (AMD) in an age-dependent fashion. J These findings provide a much-needed animal model for exploring the molecular mechanisms that lead to the development of early AMD (lipofuscin and drusen, and complement C5 and IgG deposits) and conversion to the late AMD phenotype (choroidal neovascularization (CNV) and geographic atrophy (GA", and can serve as a platform for developing and validating new therapies. As existing treatments are marginally beneficial at best, the proposed studies will provide valuable insights into the development and treatment of the human condition. We have observed that rescue of function by subretinal injection ofan adeno-associated viral (AAV) vector coding for Ccl-2 restores macrophage recruitment into the choroid and is accompanied by decreased amounts of complement component C5 and immunoglobulin G (IgG), lipofuscin, and drusen in Cel2-1-mice. More recently, we have observed greater penetrance of RPE and choroidal pathology in Cel2-!- x Ccr2-1-double knockout mice. Because macrophage scavenger receptors SR-A, SR-BI, CD36, and galectin-3 are involved in phagocytosing a wide range of endogenous ligands, we hypothesize that the accumulation of C5, IgG, drusen and lipofuscin associated with senescence in Cel2-!- x Ccr2-1-mice is due to impaired elearance by scavenger macrophages, and ultimately leads to GA and CNV. SPECIFIC AIM: To demonstrate that macrophage scavenger receptors prevent the development of AMD-like pathology by clearing aging-associated inflammatory debris. Cel2-!- x Ccrr'- mice that have been functionally rescued by subretinal AAV gene therapy, will be rendered chimerically deficient for SR-A, SR-BI, CD36, or galectin-3 by bone marrow transplantation. The effects of macrophage scavenger receptor deficiency will be explored by quantitating the accumulation ofC5 and IgG, as well as the development of lipofuscin, drusen, GA, and CNV. BACKGROUND AMD, a leading cause of blindness worldwide,2 promises to exact an even greater toll with the aging of the population. While our understanding of molecular events presaging AMD has grown in the last decade, its pathogenesis remains unresolved. Our therapeutic arsenal remains limited, in large part, due to the absence of good animal models. The experiments we propose will yield novel mechanistic data relevant to the pathogenesis of both early and late AMD, potentially leading to more effective therapies. Existing models No animal model of drusen resembling that of patients with AMD has previously been described (reviewed in ref\ Drusenlike deposits in elderly primates are dissimilar to human AMD drusen both in ultrastructural morphology and biochemical composition. Attempts to create a murine model of drusen by high fat diet, disruption of the apolipoprotein E or cathepsin D genes, inducing protoporphyria, or accelerating senescence have succeeded only in creating electron lucent debris in Bruch's membrane, but not frank drusen. The laser injury model of CNV, originally described in primates and later translated to rats and mice, has provided valuable information about the natural history ofCNV in AMD (reviewed in \ However this injury model is more likely to model the late scarring stage ofCNV in AMD than the early events in CNV development. Growing evidence suggests that vascular endothelial growth factor (VEGF) plays an important role in CNV (reviewed in \ Transgenic mice that overexpress VEGF in the photoreceptors develop new vessels originating from the deep retinal capillary bed and extending through the photoreceptor layer into the subretinal space, but not frank CNV.4,5Subretinal injection of an adenovirus or adeno-associated virus vector encoding VEGF in rats leads to CNV that breach Bruch's membrane.6,7 However, the development ofCNV in these models may be due, in part, to iatrogenic breaks in Bruch's membrane induced by subretinal injection or to inflammation and macrophage recruitment induced by adenoviruses.8 In support of this is the observation that transgenic mice with overexpression ofVEGF in the RPE do not develop CNV that penetrates through Bruch's membrane, but do so if a null adenoviral construct is introduced into the subretinal space.9 Although these powerful models represent an advance in modeling the human disease state, they are inherently constrained by their dependence on overexpressing a single growth factor, VEGF. It still is unclear whether these models adequately display the role of other cytokines and chemokines in CNV of AMD. The models we describe below (Preliminary Results) develop both early and late AMD, which to our knowledge does not occur in any other model, and also develop pathology in an age-related fashion, similar to the human condition.
|Effective start/end date||1/1/05 → 12/31/07|
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