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Huntington's Disease Repeat Instability and Pathogenesis

Award Number: R01NS049206
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: 09/01/2005
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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View Award Description

Huntington's Disease Repeat Instability and Pathogenesis - ABSTRACT Huntington’s disease (HD) is a devastating and fatal neurodegenerative disorder caused by the expansion of a polymorphic CAG repeat in the HTT gene that triggers cell death with specificity towards neurons in the striatum and cortex. Although the underlying genetic mutation was discovered over 25 years ago, there is still no cure or effective treatment despite extensive efforts. The HTT CAG repeat mutation is highly unstable both in transmissions to subsequent generations and somatically. Notably the repeat undergoes dramatic tissue- specific somatic expansion, particularly in the brain regions affected in the disorder, strongly suggesting that somatic HTT CAG length increases in target tissues contribute to HD pathogenesis. Recent human genetic data provide compelling support for somatic CAG expansion as a driver of the rate of HD pathogenesis, identifying DNA repair genes as modifiers of disease onset in HD patients, many of which modify somatic CAG expansion in accurate genetic HD knock-in mouse models. In this study, we will perform experiments to deeply interrogate these modifier genes at a number of fundamental levels. In Aim 1 we will use genetic experiments in the mouse to test the impact of altering somatic expansion on disease expression. In Aim 2, we will perform biochemical studies in patient cells and in mouse models to understand the mechanism of action and functional consequences a human modifier variant. In Aim 3 we will examine the impacts of human modifier variation on CAG instability and gene expression in specific cell types in the brain. Together, these experiments that are driven by human genetic data, will provide critical insight into mechanisms of disease modification in HD and will guide development of therapeutics targeting CAG expansion.


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 = $689,534 )
2026	2026	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	20	3/24/2026	NON-COMPETING CONTINUATION	$689,534
														Subtotal = $689,534

Issue Date FY: 2025 ( Subtotal = $620,581 )
2025	2025	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	19	3/17/2025	NON-COMPETING CONTINUATION	$620,581
														Subtotal = $620,581

Issue Date FY: 2024 ( Subtotal = $668,849 )
2024	2024	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	18	3/21/2024	NON-COMPETING CONTINUATION	$620,581
2024	2024	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	18	4/9/2024	NON-COMPETING CONTINUATION	$48,268
														Subtotal = $668,849

Issue Date FY: 2023 ( Subtotal = $689,534 )
2023	2023	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	17	4/27/2023	NON-COMPETING CONTINUATION	$689,534
2023	2022	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	16	3/13/2023	COMPETING CONTINUATION	$12,386
2023	2019	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	15	3/13/2023	NON-COMPETING CONTINUATION	-$12,386
														Subtotal = $689,534

Issue Date FY: 2022 ( Subtotal = $692,998 )
2022	2022	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	16	2/16/2022	COMPETING CONTINUATION	$692,998
2022	2019	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	15	2/9/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $692,998

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	15	5/13/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $554,553 )
2019	2019	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	15	6/27/2019	NON-COMPETING CONTINUATION	$554,553
														Subtotal = $554,553

Issue Date FY: 2018 ( Subtotal = $554,553 )
2018	2018	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	14	6/22/2018	NON-COMPETING CONTINUATION	$554,553
														Subtotal = $554,553

Issue Date FY: 2017 ( Subtotal = $584,699 )
2017	2017	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	13	7/7/2017	NON-COMPETING CONTINUATION	$584,699
														Subtotal = $584,699

Issue Date FY: 2016 ( Subtotal = $584,699 )
2016	2016	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	12	7/11/2016	NON-COMPETING CONTINUATION	$584,699
														Subtotal = $584,699

Issue Date FY: 2015 ( Subtotal = $589,694 )
2015	2015	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	11	9/17/2015	COMPETING CONTINUATION	$589,694
2015	2014	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	9/15/2015	NON-COMPETING CONTINUATION	$0
														Subtotal = $589,694

Issue Date FY: 2014 ( Subtotal = $367,842 )
2014	2014	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	4/3/2014	NON-COMPETING CONTINUATION	$367,842
														Subtotal = $367,842

Issue Date FY: 2013 ( Subtotal = $358,553 )
2013	2013	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	3/29/2013	NON-COMPETING CONTINUATION	$334,402
2013	2013	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	9	5/21/2013	NON-COMPETING CONTINUATION	$24,151
														Subtotal = $358,553

Issue Date FY: 2012 ( Subtotal = $371,557 )
2012	2012	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	3/23/2012	NON-COMPETING CONTINUATION	$371,557
														Subtotal = $371,557

Issue Date FY: 2011 ( Subtotal = $371,557 )
2011	2011	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	7	6/8/2011	NON-COMPETING CONTINUATION	$30,331
2011	2011	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	3/17/2011	NON-COMPETING CONTINUATION	$341,226
														Subtotal = $371,557

Issue Date FY: 2010 ( Subtotal = $459,184 )
2010	2010	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	7/19/2010	SUPPLEMENT FOR EXPANSION	$80,437
2010	2010	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	3/22/2010	COMPETING CONTINUATION	$378,747
														Subtotal = $459,184

Issue Date FY: 2009 ( Subtotal = $376,618 )
2009	2009	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Trans-NIH Recovery Act Research Support	001	5	7/20/2009	SUPPLEMENT FOR EXPANSION	$9,346
2009	2009	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	5/26/2009	NON-COMPETING CONTINUATION	$367,272
														Subtotal = $376,618

Issue Date FY: 2008 ( Subtotal = $367,272 )
2008	2008	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	5/21/2008	NON-COMPETING CONTINUATION	$367,272
														Subtotal = $367,272

Issue Date FY: 2007 ( Subtotal = $367,272 )
2007	2007	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	5/17/2007	NON-COMPETING CONTINUATION	$367,272
														Subtotal = $367,272

Issue Date FY: 2006 ( Subtotal = $378,242 )
2006	2006	MASSACHUSETTS GENERAL HOSPITAL	32 FRUIT STREET	BOSTON	MA	02114	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	5/26/2006	NON-COMPETING CONTINUATION	$378,242
														Subtotal = $378,242

Issue Date FY: 2005 ( Subtotal = $387,344 ) (Continued on the next page)
Grand Total All Awards = $10,035,135

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Huntington's Disease Repeat Instability and Pathogenesis

Award Number: R01NS049206

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: 09/01/2005

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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