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Contribution of RAN proteins to HD, SCA3 other CAG.CTG expansion diseases

Award Number: R01NS117910
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: 07/15/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Contribution of RAN proteins to HD, SCA3 other CAG.CTG expansion diseases - Project Summary Since we discovered repeat associated non-ATG (RAN) RAN translation in 2011, we and others have shown that RAN proteins accumulate in nine different expansion disorders. These proteins, which can be expressed from both sense and antisense expansion transcripts, accumulate in disease-relevant human tissues including spinocerebellar ataxia type 8 (SCA8) and Huntington disease (HD). We now have evidence that polySer and polyLeu RAN proteins accumulate in a group of spinocebellar ataxias (SCA1, 2, 3, 6 and 7) in which the CAG·CTG expansion mutations are located in polyGln open reading frames. Additionally, we have developed AAV and small molecule approaches to inhibit RAN translation. We will use these tools and genetic approaches to test our central hypotheses that RAN protein pathology is a common feature shared across polyglutamine encoding CAG·CTG expansion disorders and that inhibiting the PKR pathway will reduce RAN protein levels and mitigate disease. We will address our central hypothesis in three specific aims (1) To test the hypothesis that RAN proteins contribute to spinocerebellar ataxias (SCAs) caused by polyglutamine encoding CAG·CTG repeat expansion mutations. (2) To test the hypothesis that SCA and HD RAN proteins are toxic and PKR inhibition will decrease RAN protein levels and improve cellular phenotypes in HD and SCA3 iPSC derived cells (3) : To test the hypothesis that RAN proteins contribute to HD and SCA3 phenotypes in mice independent of polyGln effects using genetic and pharmacological approaches. Taken together these specific aims will determine the contribution of RAN proteins to HD,SCA3 and CAG·CTG repeat expansion disorders and characterize PKR inhibition as a potential therapeutic approach for this large class of devastating repeat expansion diseases.


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 = $683,571 )
2024	2024	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	7/26/2024	SUPPLEMENT FOR EXPANSION	$74,290
2024	2024	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	7/25/2024	NON-COMPETING CONTINUATION	$570,607
2024	2024	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	4	7/29/2024	SUPPLEMENT FOR EXPANSION	$38,674
														Subtotal = $683,571

Issue Date FY: 2023 ( Subtotal = $773,179 )
2023	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	3	7/7/2023	SUPPLEMENT FOR EXPANSION	$74,290
2023	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	3	7/8/2023	SUPPLEMENT FOR EXPANSION	$72,556
2023	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	1/4/2023	SUPPLEMENT FOR EXPANSION	$26,239
2023	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	7/3/2023	NON-COMPETING CONTINUATION	$600,094
														Subtotal = $773,179

Issue Date FY: 2022 ( Subtotal = $717,314 )
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	2	9/16/2022	SUPPLEMENT FOR EXPANSION	$72,556
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	8/19/2022	NON-COMPETING CONTINUATION	$610,876
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	1/27/2022	SUPPLEMENT FOR EXPANSION	$33,882
														Subtotal = $717,314

Issue Date FY: 2021 ( Subtotal = $610,876 )
2021	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	7/14/2021	NEW	$610,876
														Subtotal = $610,876

Grand Total All Awards = $2,784,940

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Contribution of RAN proteins to HD, SCA3 other CAG.CTG expansion diseases

Award Number: R01NS117910

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: 07/15/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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