# ConProject-001

> **NIH NIH R33** · CHAPMAN UNIVERSITY · 2021 · $723,140

## Abstract

The broad, long-term objective of the project is to develop novel therapeutic agents for spinocerebellar ataxias
(SCAs). There is no effective treatment or cure for SCAs, in large part due to insufficient understanding of the
disease pathogenesis. In this project, we will focus on spinocerebellar ataxia type 2 (SCA2). SCA2 is an
autosomal dominant genetic neurodegenerative disorder caused by polyQ expansion in ataxin-2 (Atxn2)
protein. Cerebellar Purkinje cells (PCs) are the main locus of pathology in SCA2 patients. Previously, our
laboratory discovered abnormal neuronal calcium signaling in PCs, which play an important role in the
pathogenesis of SCAs. Previous studies also suggest that neuronal activity of PCs is abnormal in ataxic mouse
models. We demonstrated that positive allosteric modulators (PAMs) of small conductance calcium-activated
potassium (SK) channels can normalize the abnormal firing pattern of PCs in SCA2 mice and alleviate
behavioral and neuropathological phenotypes. These results suggest that SK PAMs can be potentially useful
as therapeutic agents for the treatment of SCA2 and possibly for other ataxias. This project brings together the
complementary skills and expertise of two laboratories for the discovery of such agents. To achieve this goal,
we will focus on the following specific aims:
R21 Phase Aim 1. To identify novel subtype-selective SK PAM candidates. We will determine the crystal
structure of SK2 channels in complex with the prototype subtype-selective PAMs. We will obtain structural
information that will be used to perform v irtual high throughput screening for subtype-selective SK PAMs.
R21 Phase Aim 2. To validate functional activity of novel SK PAMs. We will use fluorescence-based high
throughput assay and electrophysiological methods to test SK PAM candidates.
R33 Phase Aim 3. To investigate the specificity of novel SK PAMs for SK channels. We will evaluate the
specificity of the SK PAM candidates for SK channels over other K+, Na+ and Ca2+ channels using
electrophysiological recordings.
R33 Phase Aim 4. To investigate the effects of novel SK PAMs on the activity of cerebellar PCs in SCA2
mice. We will perform ex. vivo. cerebellar slice electrophysiological recordings of PC activity in these studies.
The resulting subtype-selective SK PAMs will provide critical leads for future preclinical and clinical
development, fulfilling the critical and unmet needs in ataxia patients. These molecules will also offer novel
and unique research tools for understanding the biological function of SK channels in health and disease.
Thus, the proposed project will have significant impact in basic and translational neuroscience.

## Key facts

- **NIH application ID:** 10316591
- **Project number:** 4R33NS101182-03
- **Recipient organization:** CHAPMAN UNIVERSITY
- **Principal Investigator:** Ilya B Bezprozvanny
- **Activity code:** R33 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $723,140
- **Award type:** 4N
- **Project period:** 2017-12-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10316591

## Citation

> US National Institutes of Health, RePORTER application 10316591, ConProject-001 (4R33NS101182-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10316591. Licensed CC0.

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