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APE1 and Somatic Expansion in Huntington's Disease

Award Number: SC1NS127764
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: 02/01/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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APE1 and Somatic Expansion in Huntington's Disease - ABSTRACT Huntington’s disease (HD) is a devastating neurological disease to which no pharmacological interventions are yet available to cure the disease. HD is caused by a mutation in the huntingtin (HTT) gene consisting of an expanded CAG repeat. The age at which HD patients develop symptoms is considerably variable and although the length of the pathogenic CAG repeat correlates with age of onset, individuals with equal repeat length develop symptoms various decades after the average age of onset. This observation suggests that there are other factors beyond the CAG repeat length that can modify the development of HD symptoms, providing additional alternatives for the development of interventions to delay disease onset. Interestingly, genes involved in DNA repair have been identified as potential genetic modifiers that influence age of onset. One such candidate is APE1, the major mammalian apurinic/apyrimidinic endonuclease associated with the repair of mitochondrial DNA (mtDNA) damage, which we have shown to be a precipitating event leading to mt dysfunction, loss of motor function and neurodegeneration in HD. The expanded CAG repeat is somatically unstable and occurs during the process of repairing oxidative DNA damage. We and others have elucidated important details for APE1 and mutant HTT (mHTT) that localize to mt and reduces mt function in HD, yet our knowledge of how APE1 may contribute to the late onset in HD patients, remains incomplete. We propose that, by preventing mtDNA damage and somatic expansion, APE1 may be a genetic modifier that contributes to slowing HD age of onset. To test our hypothesis, we will study if APE1 repair activity is implicated in somatic expansion and age of onset by contributing to oxidative DNA damage and mitochondrial dysfunction. The proposed research is particularly relevant to human health, as it will deliver an unprecedented view of APE1 and mutant HTT mechanistic functions underlying HD age of onset and add the regulation of APE1 as a mechanism for future drug discovery in HD.


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: 2025 ( Subtotal = $327,094 )
2025	2025	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	B622 MAIN BUILDING FLR 6	SAN JUAN	PR	00935	SAN JUAN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	3/21/2025	NON-COMPETING CONTINUATION	$327,094
														Subtotal = $327,094

Issue Date FY: 2024 ( Subtotal = $352,535 )
2024	2024	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	B622 MAIN BUILDING FLR 6	SAN JUAN	PR	00935	SAN JUAN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	3/19/2024	NON-COMPETING CONTINUATION	$327,094
2024	2024	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	B622 MAIN BUILDING FLR 6	SAN JUAN	PR	00935	SAN JUAN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	4/10/2024	NON-COMPETING CONTINUATION	$25,441
														Subtotal = $352,535

Issue Date FY: 2023 ( Subtotal = $363,438 )
2023	2023	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	B622 MAIN BUILDING FLR 6	SAN JUAN	PR	00935	SAN JUAN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	2/28/2023	NON-COMPETING CONTINUATION	$363,438
														Subtotal = $363,438

Issue Date FY: 2022 ( Subtotal = $363,438 )
2022	2022	UNIVERSITY OF PUERTO RICO MEDICAL SCIENCES CAMPUS	MAIN BLDG FLR 6 B-622	SAN JUAN	PR	00935	SAN JUAN	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	1/27/2022	NEW	$363,438
														Subtotal = $363,438

Grand Total All Awards = $1,406,505

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APE1 and Somatic Expansion in Huntington's Disease

Award Number: SC1NS127764

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: 02/01/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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