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Understanding the Cellular Basis of Movement Disorders

Award Number: R01NS082351
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: 08/17/2013
PERIOD OF PERFORMANCE END DATE: 11/30/2029

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Understanding the Cellular Basis of Movement Disorders - Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited disorder arising from an expanded polyglutamine tract in the transcriptional repressor ATAXIN1 (ATXN1). It exemplifies two perplexing features that characterize neurodegenerative diseases as a class: SCA1 appears in adulthood, even though caused by a mutation in a gene that is expressed from development onward, and SCA1 deterioration begins in a specific brain region (in this case, the cerebellum) before spreading to other areas. We have sought to understand both these features, and this competing renewal builds on our discoveries that transcriptional dysregulation occurs in SCA1 mice within the first two weeks of life, and cerebellar neurogenesis is altered by mutant ATXN1. Much is known about the later stages of SCA1, thanks in large part to mouse models that replicate the main features of the disease. The polyglutamine expansion renders ATXN1 resistant to normal degradation pathways, and cerebellar Purkinje cells, which are the first to succumb to the disease, seem unable to handle the excess protein. (It is thought that other brain regions are able to postpone degeneration by sequestering the protein into inclusions, which are notably absent in the Purkinje neurons.) We and others found that SCA1 mice, which start to have mild incoordination on the rotarod ~3 months of age, show transcriptional alterations early in life, including downregulation of the angiogenic and neurotrophic factor VEGF. We therefore examined early cerebellar development in more detail and demonstrated that expanded ATXN1 causes cerebellar stem cells to preferentially differentiate into GABAergic molecular layer inhibitory interneurons at the expense of astrocytes, resulting in heightened GABAergic inhibition of Purkinje cells. The links in the chain from early development to symptom onset, however, remain unclear, and we must understand this pathogenic evolution in order to find viable points of intervention, as recently done for another member of the polyglutamine family, Huntington's disease. We hypothesize that early developmental perturbations are necessary to set the stage for later degeneration. To test this hypothesis, we have developed new mouse models that enable us to control the timing of mutant ATXN1 expression. We will use these mice to learn if there are certain developmental windows that are crucial for later disease onset. We will also modulate processes such as cerebellar neurogenesis to determine whether these can postpone or prevent symptom onset.


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 = $572,312 )
2026	2026	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	12	12/22/2025	NON-COMPETING CONTINUATION	$572,312
														Subtotal = $572,312

Issue Date FY: 2025 ( Subtotal = $635,901 )
2025	2025	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	11	5/14/2025	COMPETING CONTINUATION	$106,394
2025	2025	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	11	11/25/2024	COMPETING CONTINUATION	$635,901
2025	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	11/15/2024	NON-COMPETING CONTINUATION	$0
2025	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	9	5/14/2025	SUPPLEMENT FOR EXPANSION	-$3,589
2025	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	10	5/14/2025	NON-COMPETING CONTINUATION	-$102,804
														Subtotal = $635,901

Issue Date FY: 2023 ( Subtotal = $550,615 )
2023	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	10	5/21/2023	NON-COMPETING CONTINUATION	$532,040
2023	2023	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	2/8/2023	SUPPLEMENT FOR EXPANSION	$18,575
														Subtotal = $550,615

Issue Date FY: 2022 ( Subtotal = $532,040 )
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	5/27/2022	NON-COMPETING CONTINUATION	$532,040
														Subtotal = $532,040

Issue Date FY: 2021 ( Subtotal = $550,991 )
2021	2021	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	8	5/8/2021	NON-COMPETING CONTINUATION	$532,040
2021	2021	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	8	9/25/2021	SUPPLEMENT FOR EXPANSION	$18,951
2021	2019	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	10/14/2020	COMPETING CONTINUATION	-$16,115
2021	2017	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	10/14/2020	NON-COMPETING CONTINUATION	$16,115
														Subtotal = $550,991

Issue Date FY: 2020 ( Subtotal = $911,344 )
2020	2020	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	7	5/7/2020	NON-COMPETING CONTINUATION	$532,040
2020	2020	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	7	8/6/2020	SUPPLEMENT FOR EXPANSION	$379,304
2020	2019	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	1/3/2020	COMPETING CONTINUATION	$20,182
2020	2017	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	1/3/2020	NON-COMPETING CONTINUATION	-$20,182
														Subtotal = $911,344

Issue Date FY: 2019 ( Subtotal = $532,040 )
2019	2019	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	5/21/2019	COMPETING CONTINUATION	$532,040
2019	2017	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	7/18/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $532,040

Issue Date FY: 2017 ( Subtotal = $378,780 )
2017	2017	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	7/21/2017	NON-COMPETING CONTINUATION	$378,780
2017	2015	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	1/18/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $378,780

Issue Date FY: 2016 ( Subtotal = $378,780 )
2016	2016	NORTHWESTERN UNIVERSITY	633 CLARK STREET	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	6/6/2016	EXTENSION WITH OR WITHOUT FUNDS	$378,780
														Subtotal = $378,780

Issue Date FY: 2015 ( Subtotal = $378,780 )
2015	2015	NORTHWESTERN UNIVERSITY	633 CLARK STREET	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	6/9/2015	NON-COMPETING CONTINUATION	$378,780
														Subtotal = $378,780

Issue Date FY: 2014 ( Subtotal = $374,993 )
2014	2014	NORTHWESTERN UNIVERSITY	633 CLARK STREET	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	6/20/2014	NON-COMPETING CONTINUATION	$374,993
														Subtotal = $374,993

Issue Date FY: 2013 ( Subtotal = $378,780 )
2013	2013	NORTHWESTERN UNIVERSITY	633 CLARK STREET	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/9/2013	NEW	$378,780
														Subtotal = $378,780

Grand Total All Awards = $6,175,356

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Understanding the Cellular Basis of Movement Disorders

Award Number: R01NS082351

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: 08/17/2013

PERIOD OF PERFORMANCE END DATE: 11/30/2029

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