Monday, April 29, 2024
4/29/2024
Project Summary Age-related macular degeneration (AMD) coincides with retinal pigment epithelium (RPE) heterogeneity. While ordered cellular heterogeneity is beneficial, pathogenic subgroups resulted from age/stress-related heterogeneity could lead to age-related diseases. Aging and cigarette smoking (CS) are the two strongest non-genetic factors associated with AMD risk. The mechanisms whereby aging and CS drive RPE heterogeneity and these focal AMD changes are unclear. RPE mitochondrial (mt) dysfunction is a well-established pathogenic factor in AMD, and both aging and CS induce mt dysfunction. We recently reported that modest mt dysfunction from impaired mitophagy can trigger reactive oxygen species (ROS) mediated retrograde mt to nuclear signaling and RPE epithelial-mesenchymal transition (EMT), which has been identified in human AMD tissue. Senescence is a specific, terminal cellular program that induces cell cycle arrest with aging, and/or metabolic and oxidative stress. Even small numbers of senescent cells can drive age-related disease. We recently reported that mice deficient of mt phosphatase PGAM5 had mt hyperfusion, which induced significant mt dysfunction associated with changes in ROS and ATP level. As a result, a subset of RPE became senescent due to dysregulated AMPK/mTOR signaling. Similarly, our pilot data show that RPE senescence and EMT can be induced by non-lethal Cigarette Smoke Condensate (CSC). These observations suggest that mt dysfunction severity from aging/CS can initiate RPE heterogeneity. Our objective is to determine how aging and smoking induced mt dysfunction severity triggers RPE heterogeneity including EMT and senescence, to link these phenotypes with RPE dysfunction and an AMD phenotype in animal models, and identify the molecular identity of RPE heterogeneity including EMT and senescence in a smoking model of AMD and human AMD samples. Our hypothesis is that RPE mt dysfunction severity from smoking and aging induces RPE heterogeneity including EMT, senescence, and cell death, which will be tested in two specific aims (SA). SA I is to determine the extent that mt dysfunction severity from aging drives RPE heterogeneity through regulating mt dynamics. SA II is to determine the extent that mt dysfunction severity from smoking, especially when combined with aging, promotes RPE heterogeneity and an AMD phenotype. By the end of proposed project, we will have experimentally linked mt dysfunction severity with RPE EMT, senescence, and cell death, and identified therapeutic targets to test for dry AMD, a long-term goal of our labs.
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