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Development of SK channel modulators as therapeutic agents for ataxia

Award Number: R33NS101182
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2017
PERIOD OF PERFORMANCE END DATE: 04/30/2023

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Development of SK channel modulators as therapeutic agents for ataxia - 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 virtual 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = -$6 )
2024	2021	CHAPMAN UNIVERSITY	1 UNIVERSITY DR	ORANGE	CA	92866	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	1/22/2024	EXTENSION WITH OR WITHOUT FUNDS	-$6
														Subtotal = -$6

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	CHAPMAN UNIVERSITY	1 UNIVERSITY DR	ORANGE	CA	92866	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	12/22/2022	EXTENSION WITH OR WITHOUT FUNDS	$0
2023	2021	CHAPMAN UNIVERSITY	1 UNIVERSITY DR	ORANGE	CA	92866	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	3	8/25/2023	EXTENSION WITH OR WITHOUT FUNDS	$0
2023	2021	CHAPMAN UNIVERSITY	1 UNIVERSITY DR	ORANGE	CA	92866	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	8/21/2023	EXTENSION WITH OR WITHOUT FUNDS	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $723,146 )
2021	2021	CHAPMAN UNIVERSITY	ONE UNIVERSITY DR	ORANGE	CA	92866	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	7/26/2021	EXTENSION WITH OR WITHOUT FUNDS	$6
2021	2021	CHAPMAN UNIVERSITY	ONE UNIVERSITY DR	ORANGE	CA	92866	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	12/29/2020	EXTENSION WITH OR WITHOUT FUNDS	$723,140
														Subtotal = $723,146

Grand Total All Awards = $723,140

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Development of SK channel modulators as therapeutic agents for ataxia

Award Number: R33NS101182

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 12/01/2017

PERIOD OF PERFORMANCE END DATE: 04/30/2023

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