# Selective neurovascular regulation by a vascular dementia-related noncoding RNA Snord118

> **NIH NIH R21** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2022 · $467,471

## Abstract

PROJECT SUMMARY/ABSTRACT
Dysfunction of neurovascular unit (NVU) is a key pathological event of neurodegenerative diseases, including
Alzheimer's disease and Alzheimer's disease-related dementias (AD/ADRD). The mechanism underlying cell-
type selective vulnerability in NVU is poorly understood. The goal of this proposal is to establish a novel
mechanism by which NVU cell(s) are selectively impaired by the disruption of a global ribosome biogenesis.
We will focus on a newly identified ribosomopathy disease gene Snord118, which encodes a noncoding RNA
acting as a ribosome biogenesis factor. This is interesting because Snord118 mutations cause the first purely
neurological disorder in ribosomopathies, named leukoencephalopathy with calcifications and cysts (LCC), with
NVU lesions. There is very little understanding of Snord118 and LCC pathogenesis. This study has an
opportunity to determine functions and mechanisms of Snord118 and LCC disease. We have assembled the
following preliminary data: 1) generated two disease point mutation knock-in (KI) mice, which display early
pericyte and BBB defects. These results suggest that brain endothelial cells (ECs) and pericytes are selectively
affected in LCC, which justifies our iPSC research focus on brain ECs and pericytes; 2) generated five
Snord118 mutant iPSC lines with isogenic controls, established protocols of directing iPSCs into brain
microvascular endothelial cells (BMECs) and pericytes with the CNS identities, and prepared functional assays
for BMEC, pericyte, and blood-brain barrier (BBB) properties; 3) developed the PARIS method to high
throughput map RNA structures and identify RNA targets at single molecule and genome-wide levels with
base-pair resolution. Our PARIS revealed a dynamic RNA structure and interaction network in Snord118
ribosome biogenesis and LCC. Leveraging on these preliminary data and tools, we propose to test the
hypothesis that Snord118 mutation-mediated disruption of ribosome biogenesis selectively affects BMECs and
pericytes via targeting rRNAs and non-rRNAs. Aim 1 will determine cellular functions of Snord118 in
neurovascular cells focusing on BMECs and pericytes. Aim 2 will identify Snord118 targets and its RNA
structure-function relationships. Overall, using our new iPSC-derived NVU cells and latest PARIS2, this study
will generate the first human cellular models that do not currently exist for SNORD118 LCC, identify
mechanisms of SNORD118 action and LCC disease, uncover a previously unknown vulnerability of specific
NVU cells to the disruption of a ubiquitous ribosome biogenesis process, and therefore help to reconcile the
neurological phenotype specificity of ribosomopathies with the global requirement for ribosome biogenesis.

## Key facts

- **NIH application ID:** 10435866
- **Project number:** 1R21AG070681-01A1
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Jianfu Chen
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $467,471
- **Award type:** 1
- **Project period:** 2022-05-15 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10435866

## Citation

> US National Institutes of Health, RePORTER application 10435866, Selective neurovascular regulation by a vascular dementia-related noncoding RNA Snord118 (1R21AG070681-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10435866. Licensed CC0.

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