Age-related macular degeneration (AMD) is the leading cause of blindness in people over 50 years of age in the industrialized world. Vision loss in advanced AMD is either due to pathologic angiogenesis called choroidal neovascularization (CNV) or from loss of the retinal pigmented epithelium and overlying photoreceptor neurons in geographic atrophy. CNV tends to be catastrophic and accounts for about 80-90% of severe vision loss in AMD. Macrophage-mediated inflammation plays a critical role in the pathogenesis of CNV in AMD. The aging macrophage manifests its dysfunction in AMD by altered activation and polarization. The regulatory mechanisms that govern gene expression changes within macrophages are poorly characterized. MicroRNAs regulate gene expression at a global level but with cellular specificity and do so by mRNA degradation and translational repression. We propose to examine which miRNAs are altered in the aging macrophage, identify the specific gene targets that they regulate and assess the effects of modifying both the miRNA and genes in macrophages on their fate, function and ability to regulate CNV. This could be especially insightful as it might confirm age as a continuous variable that can be quantitatively regulated at an intrinsic level. We hope to identify novel miRNA, genes and molecular pathways that could be therapeutically targeted in AMD to prevent vision loss in this devastating disease.
Altered macrophage polarization is a pathogenic event in the aging of the immune system. It is also critical to the pathobiology of diverse diseases of aging including age-related macular degeneration (AMD). Although abnormalities in macrophage function in AMD have been phenotypically characterized, the molecular pathways that regulate this phenotype are unclear. The current proposal will focus on understanding how small non-coding microRNAs regulate aging macrophage gene expression. Understanding the regulation of genes involved in AMD pathogenesis will open up novel avenues for targeted therapy for this devastating disease.
| Ban, Norimitsu; Lee, Tae Jun; Sene, Abdoulaye et al. (2018) Impaired monocyte cholesterol clearance initiates age-related retinal degeneration and vision loss. JCI Insight 3: |
| Lin, Jonathan B; Kubota, Shunsuke; Mostoslavsky, Raul et al. (2018) Role of Sirtuins in Retinal Function Under Basal Conditions. Adv Exp Med Biol 1074:561-567 |
| Lin, Jonathan B; Apte, Rajendra S (2018) NAD+ and sirtuins in retinal degenerative diseases: A look at future therapies. Prog Retin Eye Res 67:118-129 |
| Lin, Joseph B; Sene, Abdoulaye; Wiley, Luke A et al. (2018) WNT7A/B promote choroidal neovascularization. Exp Eye Res 174:107-112 |
| Ban, Norimitsu; Siegfried, Carla J; Apte, Rajendra S (2018) Monitoring Neurodegeneration in Glaucoma: Therapeutic Implications. Trends Mol Med 24:7-17 |
| Ban, Norimitsu; Lee, Tae Jun; Sene, Abdoulaye et al. (2018) Disrupted cholesterol metabolism promotes age-related photoreceptor neurodegeneration. J Lipid Res 59:1414-1423 |
| Cheung, Chui Ming Gemmy; Gan, Alfred; Fan, Qiao et al. (2017) Plasma lipoprotein subfraction concentrations are associated with lipid metabolism and age-related macular degeneration. J Lipid Res 58:1785-1796 |
| Ban, Norimitsu; Siegfried, Carla J; Lin, Jonathan B et al. (2017) GDF15 is elevated in mice following retinal ganglion cell death and in glaucoma patients. JCI Insight 2: |
| Apte, Rajendra S (2016) Targeting Tissue Lipids in Age-related Macular Degeneration. EBioMedicine 5:26-7 |
| Park, Changwon; Lee, Tae-Jin; Bhang, Suk Ho et al. (2016) Injury-Mediated Vascular Regeneration Requires Endothelial ER71/ETV2. Arterioscler Thromb Vasc Biol 36:86-96 |
Showing the most recent 10 out of 23 publications
