Molecular Mechanisms of Subretinal Debris Removal in the Ccr2-/- Mouse Model of AMD

  • Ambati, Jayakrishna (PI)

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Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly in the U.S., affecting more than 11 million individuals. Absence of good animal models has limited mechanistic understanding and thwarted development of therapies. We recently reported that mice deficient in the macrophage chemoattractant receptor Ccr-2 gene develop AMD similar to humans (Ambati J. et al. Nature Medicine 2003; 9: 1390-7). This animal model reproduces most of the salient features of human AMD. As in patients with AMD, inflammatory proteins such as complement components and immunoglobulins are deposited in subretinal tissues of these mice. We have shown that accumulation of these inflammatory deposits results from an inability to recruit ~~~vengermacrophages that normally maintain homeostasis by degrading these toxins, which contribute to the development of AMD. We propose to explore the role of scavenger receptors used by macrophages to clear these deposits to define the molecular mechanisms underlying the development of AMD in Ccr-2 deficient (knockout) mice. Using bone marrow transplantation, we will rescue the function of the Ccr-2 gene in knockout mice to inhibit development of AMD, and simultaneously eliminate expression of macrophage scavenger receptors to determine their contribution in preventing the inhibition of AMD induced by gene therapy. The data emerging from this study will reveal novel information about the molecular mechanisms of AMD, and provide new therapeutic targets and biomarkers for this blinding disease.
Effective start/end date1/1/056/30/06


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