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Targeting Cerebellar Endoplasmic Reticulum Calcium Handling in Essential Tremor

Award Number: R01NS124854
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: 12/15/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Targeting Cerebellar Endoplasmic Reticulum Calcium Handling in Essential Tremor - PROJECT SUMMARY/ ABSTRACT Essential tremor (ET) is the most common tremor disorder, affecting 2.2% of the total US population. ET is also a progressive disorder, with tremor becoming more severe over time. Despite its high prevalence, therapeutic options for ET are far from satisfactory, in part due to an unclear understanding of disease mechanisms, leaving many patients disabled. Through long-term NIH funded efforts to collect postmortem ET brains, we have identified morphological changes in the ET cerebellum that reflect cellular damage in Purkinje cells (PCs). Recent converging evidence of genetics and neuropathology has identified a role for abnormal endoplasmic reticulum (ER) calcium handling in ET. Specifically, a key ER calcium channel called ryanodine receptor type 1 (RyR1), which is expressed in PCs in cerebellar cortex, undergoes site-specific phosphorylation and in this state becomes leaky. We found that ET cerebellum has markedly increased levels of phosphorylated RyR1, which is not seen in control or Parkinson’s cerebellum, creating a chronic ER calcium leak state in the ET cerebellum. We established a mouse model harboring a point mutation in RyR1 that mimics constitutive site- specific phosphorylation, recapitulating the RyR1 leaky phenotype (RyR1-S2844D “leaky” mice), and this mouse model develops altered cerebellar physiology and progressive ET-like tremor. These findings support that abnormal ER calcium handling contributes to tremor. However, the detailed mechanism how abnormal ER calcium handling leads to tremor and whether its manipulation can be used to treat tremor remains unclear, which is a major obstacle for therapy development. Towards solving this knowledge gap, we propose to test the hypothesis that dysfunctional ER calcium handling leads to structural and physiological alterations in cerebellum that drive tremor. In the proposed five year study, we will use both mouse models (Aim 1, Aim 2) and postmortem human ET brains (Aim 3) to address the role of ER calcium handling for tremor generation: Aim 1: We will determine how specific structural and physiological changes in cerebellar PCs of RyR1-leaky mice play a role in tremor emergence and progression. Aim 2: We will determine if bi-directional modulation of ER calcium handling alters PC physiology and tremor in RyR1-leaky mice and examine the PC specificity of these alterations. Aim 3: We will determine whether the upstream regulators for RyR1 biochemical remodeling and the degree of RyR1 leakiness are altered in the postmortem human ET cerebellum and correlate these metrics with tremor severity and PC pathologic changes. These data will advance our understanding of ET from observational studies into mechanistic insight, which will serve as scientific rationale for therapy development.


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: 2026 ( Subtotal = $527,173 )
2026	2026	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	12/15/2025	NON-COMPETING CONTINUATION	$527,173
														Subtotal = $527,173

Issue Date FY: 2025 ( Subtotal = $528,700 )
2025	2025	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	11/27/2024	NON-COMPETING CONTINUATION	$528,700
														Subtotal = $528,700

Issue Date FY: 2024 ( Subtotal = $595,333 )
2024	2024	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	11/22/2023	NON-COMPETING CONTINUATION	$552,371
2024	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	4/11/2024	NON-COMPETING CONTINUATION	$42,962
														Subtotal = $595,333

Issue Date FY: 2023 ( Subtotal = $612,569 )
2023	2023	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	11/23/2022	NON-COMPETING CONTINUATION	$551,313
2023	2023	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	1/30/2023	NON-COMPETING CONTINUATION	$61,256
														Subtotal = $612,569

Issue Date FY: 2022 ( Subtotal = $603,504 )
2022	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/15/2021	NEW	$603,504
														Subtotal = $603,504

Grand Total All Awards = $2,867,279

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Targeting Cerebellar Endoplasmic Reticulum Calcium Handling in Essential Tremor

Award Number: R01NS124854

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: 12/15/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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