# Alzheimer's disease-linked microRNA Exploration of UTR Polymorphisms (AdmiRE-UP)

> **NIH NIH R21** · INDIANA UNIVERSITY INDIANAPOLIS · 2022 · $435,349

## Abstract

Effective treatments are urgently needed to cure or delay Alzheimer’s disease (AD). Major hallmarks of AD
are extracellular plaque deposits of amyloid-β (Aβ) peptide, which is derived from the Aβ precursor protein (APP),
and intracellular tangles of hyperphosphorylated tau protein. Further, myeloid cells may be involved, such as
implied by connections between AD and the TREM2 protein. APP, tau, and TREM2 expression are regulated by
non-coding microRNA (miRNA), via targets in their mRNAs. Several single-nucleotide polymorphisms (SNP)
associate with AD. We hypothesize that naturally occurring SNPs within the UTR sequences by altering miRNA
recognition sites can alter risk and/or progression of AD. We propose to test miRNAs that 1) are experimentally
confirmed to alter AD-related protein levels, 2) have experimentally verified targets in these mRNAs, and 3) have
perturbed levels in human AD brain. We propose a systematic Alzheimer’s disease-linked microRNA exploration
of UTR polymorphisms (AdmiRe-Up) to elucidate effects of these variations. Our innovation is to assess
naturally-occurring polymorphisms (SNPs) in miRNA target sites for functional activity in relation to disease.
Novel AdmiRe-Up platform rationally winnows candidate polymorphisms through successive stages. Our
outcome is to functionally validate known naturally-occurring polymorphisms in confirmed miRNA sequences in
the UTRs, employing three specific aims (SA). SA1: Test hypothesis—naturally occurring SNPs alter reporter
response to miRNA. SA2: Test hypothesis—naturally occurring SNPs alter target protein levels in response to
miRNA treatment. SA3: Test hypothesis—naturally, occurring SNPs alter target protein levels in response to
miRNA treatment in human induced pluripotent stem (iPS) cells.
 The AdmiRe-Up platform requires a SNP be within an miRNA target sequence that 1) has been experimentally
confirmed to alter target protein levels; 2) was experimentally validated for sequence; and 3) has perturbed levels
in association with AD. Variants will then be cross-indexed with disease genomic variation databases to prioritize
already-reported associations. SNPs that pass these criteria will be used for dual-reporter based functional
assays. SNPs activity that differ from wildtype will be used as templates to engineer chromosomal mutants in
cell cultures. SNPs that pass these stages would then be used in disease-specific iPS cells from clinical sources.
We expect each successive step of the process to produce a tightening circle of “active” variants. Those variants
that still show significant difference from wildtype APP will then be searched for in the ADNI database for potential
associations with AD-associated phenotypes.
 Within the limits of an R21, proof of the concept will lay a path for rigorous and systematic exploration of
functional effects of SNPs in the UTR sequences of uncounted other disease-associated genes. A systematic
method, AdmiRe-Up, of testing polymorphism effects o...

## Key facts

- **NIH application ID:** 10391153
- **Project number:** 1R21AG074539-01A1
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** DEBOMOY K LAHIRI
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $435,349
- **Award type:** 1
- **Project period:** 2022-03-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10391153

## Citation

> US National Institutes of Health, RePORTER application 10391153, Alzheimer's disease-linked microRNA Exploration of UTR Polymorphisms (AdmiRE-UP) (1R21AG074539-01A1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10391153. Licensed CC0.

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