Splice-switching antisense oligonucleotides (SSOs) as a senomorphic intervention

National Institute On Aging

Investigators

Abstract

Alternative splicing is an indispensable mechanism that generates proteome complexity in many organisms and appears to have a functional role in many biological processes including aging. In the FY2202-funded project, we proposed to use Single-cell Nanopore sequencing with UMIs (ScNaUmi-seq) to systematically dissect full-length isoform variations in single cells in three models: cellular senescence in cell culture, in vivo normal aging, and age-related atherosclerosis. We identified that transcript variants for ribosome subunits are differentially expressed in proliferating and senescent human fibroblasts as well as in a celltype-specific manner in mouse aortas. In the current proposal, we will focus on characterizing thefunctional roles of alternatively spliced mRNA isoforms. We also plan to develop a novel strategy to increase throughput and sensitivity of ScNaUmi-seq. Finally, we will extend our survey to cell-to-cell isoform variations in tissues in normal aging. This work will allow in-depth characterization of full-length isoform diversity in senescence and aging, advancing our understanding of the roles and mechanisms of RNA splicing in normal aging and age-related disorders.