Sunday, May 18, 2025
5/18/2025
Histone Expression in the Aging RPE - Project Summary (30 lines): Aging is a complex, multifactorial process wherein transcriptional reprogramming is accompanied by perturbations in the epigenome. We have performed experiments to determine the histone expression profile in the aging RPE and discovered an age-dependent loss of histone expression that was specific to the RPE. It is not known whether loss of histone expression during RPE aging alters gene expression, induces cell death, or leads to the progression of age-related macular degeneration (AMD). AMD is a blinding disease that is hallmarked by the death of retinal pigment epithelium (RPE), choroidal neovascularization, and loss of the overlying photoreceptors in the central retina. Several recent scientific advances have revealed an array of molecular mechanisms that result in RPE atrophy including disinhibition of the alternate complement pathway, inflammasome activation, and the expression of pro-apoptotic signaling components Tight histone which serve expression to histone be regulatory regulation of expression is essential to maintain chromatin structure and appropriate gene expression profiles are critical to cell viability and function. Moreover, post-translational modifications (PTM) of histones as critical mechanisms for epigenetic regulation of gene expression. Decreased histone gene and altered histone PTMs have been identified as a molecular hallmark of aging. The Objective is define signatures of histone expression in the aging RPE and determine the cellular effects of loss of expression in RPE homeostasis and AMD progression. The Hypothesis is that histone depletion may a key factor contributing to RPE aging and senescence and that therapeutic targeting of key histone mechanisms ma serve as a valuable approach to reverse aging and senescence in the RPE. Using RNA-seq, ChIP-seq, high-throughput screening of histone PTMs, Western blotting, and immunofluorescence SA1 homeostasis blotting, RPE histone whether and further in and evaluates histone expression profiles and marks to identify critical regulatory factors o histone in the aging mouse RPE. Using RNA-seq, high-throughput screening of histone PTMs, Western and immunofluorescence, and immunohistochemistry, SA2 i nterrogates in vitro models of human aging, aged normal human eyes and eyes with advanced dry AMD for loss of histone expression, modifications, and molecular mechanisms of histone related cell death. Further work will demonstrate restoration of specific histone isoforms or histone regulatory factors will reverse aging, senescence restore RPE cell viability in mouse and cell culture models. These data will be critical to developing scientific insight into the critical role of tightly regulated histone gene expression in the aging RPE and AMD progression while offering a novel therapeutic approach to maintaining RPE health, genomic fidelity, cellular integrity. f
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