Thursday, April 3, 2025
4/3/2025
Nuclear encoded Humanin Isoforms and Mitochondria in Age-related Macular Degeneration - Age-related macular degeneration (AMD) is a leading cause of blindness in the aging population due to the continuous deterioration of macular RPE and retina in the advanced stages of the disease including geographic atrophy (GA) and neovascular AMD (nAMD). In nAMD, the anti-VEGF therapy effectively reduces the incidence of blindness in some patients, but fails in others. Identifying new molecular targets for developing treatment to prevent the onset of nAMD is thus an urgent and unmet need. In this proposal, we will target this knowledge gap focusing on MTRNR2L1, a novel nuclear encoded humanin isoform gene. In a recent RNA sequencing study, we identified MTRNR2L1 as the top upregulated gene in the macular RPE and retina from human donor eyes with intermediate AMD or nAMD. Moreover, our preliminary study demonstrated that MTRNR2L1 expression is significantly upregulated in RPE cells by several factors related to AMD pathogenesis including oxidative stress, hypoxia, and inflammation. Despite a high sequence similarity and a similar tissue expression pattern with humanin, the biological function of MTRNR2L1 is currently unknown. Thus, in this application we seek to elucidate the function of MTRNR2L1 in human RPE and choroidal cells and explore its potential implication in nAMD pathogenesis. Specifically, we will address whether MTRNR2L1 is a protein-encoding gene or a lncRNA using molecular biology approach and elucidate the role of MTRNR2L1 in mitochondrial regulation and cell survival in RPE cells exposed to endoplasmic reticulum (ER) and oxidative stress in early AMD. Furthermore, we will determine if MTRNR2L1 plays a role in the regulation of pro-angiogenic factor production from RPE cells and in the regulation of angiogenic activities of choroidal endothelial cells. We anticipate that the proposed studies will provide proof-of-concept evidence for a novel role of MTRNR2L1 as a molecular target in the AMD progression and transition to nAMD. The findings will also lay a foundation for future studies on other nuclear humanin isoform genes in AMD and beyond.
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