# Identifying New Astrocytic Kir4.1 Channel Modulators for Treating Huntington's Disease

> **NIH NIH R21** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $211,250

## Abstract

Summary
Huntington's Disease (HD) is a neurodegenerative disease that is characterized by progressive impairments of
motor and cognitive functions, leading to uncontrolled movements (chorea), dementia and reduced life
expectancy. An inherited mutation in the Huntington protein (Htt) underlies HD, leading to intracellular
accumulation and aggregation, with extensive neurodegeneration in the basal ganglia, specifically GABAergic
medium spiny neurons (MSNs). There are currently no treatments for HD. Recent studies have focused on the
role of astrocytes in HD. In particular, the inwardly-rectifying potassium channel Kir4.1 is downregulated in
striatal astrocytes of mice with HD, leading to hyperexcitability of MSN neurons. EEAT2 expression and
function are also impaired in HD mice. We hypothesize that a selective small molecule Kir4.1 activator could
enhance endogenous Kir4.1 activity, and potentially lead to a novel treatment for HD. To address this, we
propose to (1) identify new small molecule pharmacophores of Kir4.1 channels using an innovative approach
of virtual screening and unique modulatory sites in Kir4.1 channels, and (2) assess the effect of these small
molecule Kir4.1 pharmacophores on an astrocytic-neuronal function and HD mice. These experiments will
provide the foundation for new studies probing the role of Kir4.1 in HD.

## Key facts

- **NIH application ID:** 10817090
- **Project number:** 5R21NS130886-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Avner Schlessinger
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $211,250
- **Award type:** 5
- **Project period:** 2023-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10817090

## Citation

> US National Institutes of Health, RePORTER application 10817090, Identifying New Astrocytic Kir4.1 Channel Modulators for Treating Huntington's Disease (5R21NS130886-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10817090. Licensed CC0.

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