# Mechanism of STING-mediated Neuropathology in Niemann-Pick Disease

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2021 · $481,299

## Abstract

Niemann-Pick disease type C (NPC) is a fatal neurodegenerative disease caused by genetic mutations in the
NPC1 (95%) and NPC2 (5%) genes. Neurological features of NPC bear striking resemblances with Alzheimer’s
disease (AD), leading to some experts considering NPC as “Childhood Alzheimer’s”. No FDA-approved therapy
is available. Lipids and cholesterol defects associated with the NPC disease are well understood. However,
immune pathways underlying neuroinflammation and Purkinje cell death in the NPC disease remain unknown.
We recently found that the innate immune STING pathway is activated by NPC-deficiency, and genetic deletions
of STING pathway components in mice are able to remarkably rescue NPC neuropathology. The overall goal of
this project is to understand how STING drives neuropathology associated with the NPC disease. Aim 1 will
focus on intracellular mechanisms, where we will dissect how STING signaling is activated by NPC-deficiency.
Aim 2 will focus on brain tissue pathology, where we will comprehensively determine STING expression cell
types, activities and their functional contribution to the NPC disease. Aim 3 will focus on therapeutic assessment,
where we will treat Npc1-/- mice and NPC1 patient iPSC-derived cells with existing and new STING pathway
inhibitors. STING has been implicated in several neurodegenerative diseases including Parkinson’s disease,
ALS/FTD and now NPC1. Studies proposed here will provide a much-needed comprehensive understanding of
STING pathway function in the brain as well as a step-by-step mechanism from STING activation to
neuropathology.

## Key facts

- **NIH application ID:** 10274942
- **Project number:** 1R01NS122825-01
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Nan Yan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $481,299
- **Award type:** 1
- **Project period:** 2021-08-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10274942

## Citation

> US National Institutes of Health, RePORTER application 10274942, Mechanism of STING-mediated Neuropathology in Niemann-Pick Disease (1R01NS122825-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10274942. Licensed CC0.

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