Thursday, May 29, 2025
5/29/2025
Leveraging large-scale genomics to dissect A-to-I editing in brain aging and Alzheimer's disease - PROJECT SUMMARY Post-transcriptional modifications through adenosine-to-inosine (A-to-I) editing are critical for maintaining the diverse repertoire of RNA transcripts in the human brain. These modifications occur at isolated adenosines and across multiple consecutive adenosines within an extended region along the same RNA molecule. A-to-I editing influences gene function, alternative splicing, protein sequences, miRNA binding, and RNA structures. Recent work by us and others show that A-to-I editing is abundant during normal aging and changes in editing levels are tied to etiology of Alzheimer’s disease and related dementias (AD/RD). Nevertheless, substantial gaps persist regarding the precise roles and implications of A-to-I editing in AD/RD. For instance, the majority of A-to- I sites are expected to undergo dynamic regulation within a common double-stranded (ds)RNA structure throughout the progression of normal aging and dementia severity. However, our understanding of this context- dependent regulation of RNA editing is currently limited. Moreover, the role of common genetic variation on the regulation of A-to-I editing levels (editing quantitative trait loci [edQTLs]), as well as their impact on A-to-I sites en masse along a shared dsRNA structure, has been significantly understudied. There has also been a dearth of experimental tools that precisely probe the function of candidate A-to-I sites. We will bridge the existing knowledge gaps through a comprehensive approach that will: Aim 1) Address the unmet need for basic neuroscientific research that can capture fundamental regulation of RNA editing across brain development, normal aging and in AD/RD; Aim 2) Integrate individual genetic information to construct robust maps of edQTLs and identify AD/RD risk loci that modulate A-to-I editing levels and dsRNA structures across ancestries and cell types; Aim 3) Establish a systematic and biologically validated prioritization of AD/RD-associated A-to-I sites, using an integrative computational approach together with a site-directed RNA editing molecular toolbox. Capitalizing on the significant progress made by large-scale consortia initiatives, we will investigate the functional and regulatory roles of A-to-I editing in AD/RD with unprecedented scale and depth. Results from this proposal will reveal more nuanced and accurate insights into the molecular and genetic underpinnings of AD/RD pathobiology, paving the way for the identification of novel therapeutic targets for these devastating neurodegenerative diseases.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).