# Circular RNAs and their interactions with RNA-binding proteins to modulate AD-related neuropathology

> **NIH NIH U01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2022 · $769,284

## Abstract

SUMMARY
New variants, especially in non-coding regions, are expected to be discovered through the ongoing AD
Sequencing Project (ADSP). This proposal will investigate circular RNAs (circRNAs) and RNA binding proteins
(RBPs) that regulate or are regulated by these circRNAs. Recent genomic studies have discovered thousands
of circRNAs produced from both protein-coding genes and non-coding regions of the genome via a process
known as back-splicing. CircRNAs are more enriched in neuronal tissues and are often derived from genes
specific for neuronal and synaptic function. The discovery of these circRNAs demands a coordinated
investigation of RBPs that interact with the circRNAs. Mutations in and dysfunction of RBPs are known to be
major mechanisms contributing to the pathophysiology in frontotemporal dementia, ALS and AD. However, the
contributions of the circRNA:RBP network to these disease mechanisms are largely unknown. The novel
biology of circRNAs opens an entirely new window into mechanisms of neurodegeneration in ADRD. CircRNAs
could contribute to neurodegeneration by acting as sponges that sequester miRNA/RBPs away from normal
mRNA targets, altering splicing or expression. RBPs also regulate circRNA production by binding to the
flanking intronic sequences of circRNAs which contain many conserved binding sites of splicing factors/RBPs.
Thus, sequestration of RBPs in protein aggregates could cause dysfunctional regulation of circRNAs. The
history of genomics indicate that discovery of each new nucleotide species expands our understanding of
disease mechanisms. The discovery of circRNA presents a major unexplored avenue of RNA metabolism that
demands investigation. We hypothesize that changes in the levels of circRNAs contributes to the
pathophysiology of ADRD, and that discovery of key circRNAs or circRNA-RBP interactions in aging
human brains could uncover novel biomarkers, disease mechanisms or therapeutic targets. In this
proposal, by leveraging large public and our own RNA-seq data (rRNA-depleted), we will apply several
methods to detect and characterize AD-related circRNAs from multiple human brain regions, and integrate
them with ADSP genetic findings (Aim 1). In Aim 2, aside from discovering AD-related RBPs from human brain
RNA-seq, proteomics and ADSP WES/WGS data, we will leverage the ENCODE CLIP-seq data for RBP
binding to identify putative RBP-circRNA interactions with AD, i.e. AD-related functional RNA elements. Finally,
in Aim 3, we will select the top 10% of the circRNAs (~200) and RBPs (~150) for further high-throughput
functional evaluation with a novel, powerful 3D human organoid model of ADRD, termed AstAD that exhibits
the full range of tau pathology and neurodegeneration. We anticipate that our integrative analyses of ADSP
genetics, circRNA, mRNA, RBP and the high-throughput AstAD functional screen readouts can help generate
testable hypothesis for future molecular mechanisms experimental design.

## Key facts

- **NIH application ID:** 10436271
- **Project number:** 5U01AG072577-02
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Benjamin L Wolozin
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $769,284
- **Award type:** 5
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10436271

## Citation

> US National Institutes of Health, RePORTER application 10436271, Circular RNAs and their interactions with RNA-binding proteins to modulate AD-related neuropathology (5U01AG072577-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10436271. Licensed CC0.

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