Grant: Project Grant

Age-related Macular degeneration (AMD) is the leading cause of adult vision loss. AMD presents itself in dry and wet clinical forms. The early phase of the dry form is characterized by thickening of membranes in the sub-retina, a middle layer of the wall of the eye, between the white outer layer of the eye called the sclera and the inner layer of nerve tissue at the back of the eye called the retina. Such thickening is accompanied by a loss of photoreceptors (light detecting cells) and recruitment of white blood cells called macrophages. The wet form of AMD is characterized by increased and erratic growth of blood vessels in the choroid near the so-called macula which is the part of the retina which has a high density of photoreceptor cells responsible for central vision. Macrophages engulf and digest damaged tissue by a process called phagocytosis, that triggers signalling pathways leading to inflammation. Macrophage response to damaged cells is central for maintaining healthy tissue. During macular degeneration, however, exaggerated macrophage function can aggravate inflamed tissue by creating reactive oxygen species and amplifying inflammation thus causing further tissue damage. Our lead molecules can modulate macrophage activity and have pertinent potential to enhance clearance of cellular debris without generating reactive oxygen species and accrued inflammatory factors. Our lead compounds target the so-called CD36 scavenger receptor, which is commonly found on the surface of macrophages and integrally engaged in the absorption of oxidized lipid and lipoprotein debris. To establish clinically effective protocols for treating AMD, the proposed research will perform studies in mice to establish the dosage and toxicity of lead compounds. The scaled-up synthesis of lead compound will be developed for preparing quantities for clinical trials. Moreover, a predictive computational method will be conceived to design backups with optimal properties to treat AMD.