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Loss of siRNA based gene silencing and retrotransposon activation in TDP-43 mediated neurodegeneration

Award Number: R01NS091748
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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¿ DESCRIPTION (provided by applicant): The TDP-43 protein plays a role in a broad suite of neurodegenerative disorders including Frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis, and potentially, Alzheimer's disease. TDP-43 is a multifunctional protein with many known cellular roles. So, while the importance of TDP-43 in neurodegeneration is established, the mechanisms of TDP-43 toxicity are unclear. We have discovered a new role for TDP-43 in regulating small-RNA based gene silencing, which is critical to block expression of retrotransposons. Retrotransposons are virus-like sequences that are encoded in our genomes and are capable of replicating and inserting at new chromosomal positions. The toxic potential of transposons in the germline is established. So our discovery provides a plausible hypothesis for toxic effects of TDP-43 in neurons. Our preliminary studies provide strong evidence that TDP-43 normally helps to silence transposons and that this function is disrupted both in FTLD patients and a Drosophila disease model. Our proposed experiments will use genetic manipulations in Drosophila to test three key specific hypotheses: 1) that TDP-43 pathology disrupts argonaute-2 mediated silencing; 2) that TDP-43 pathology activates retrotransposons in Drosophila brain; 3) that Retrotransposon activation contributes to neurodegeneration


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: 2020 ( Subtotal = -$15,442 )
2020	2019	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	5/8/2020	NON-COMPETING CONTINUATION	-$15,442
														Subtotal = -$15,442

Issue Date FY: 2019 ( Subtotal = $347,660 )
2019	2019	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	11/23/2018	NON-COMPETING CONTINUATION	$347,660
														Subtotal = $347,660

Issue Date FY: 2018 ( Subtotal = $347,028 )
2018	2018	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	4/26/2018	NON-COMPETING CONTINUATION	$34,704
2018	2018	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	11/8/2017	NON-COMPETING CONTINUATION	$312,324
														Subtotal = $347,028

Issue Date FY: 2017 ( Subtotal = $345,313 )
2017	2017	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	4	7/10/2017	NON-COMPETING CONTINUATION	$34,533
2017	2017	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	12/6/2016	NON-COMPETING CONTINUATION	$310,780
2017	2016	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	3	1/23/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$75,477
2017	2016	COLD SPRING HARBOR LABORATORY	1 BUNGTOWN RD	COLD SPRING HARBOR	NY	11724	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	1/23/2017	NON-COMPETING CONTINUATION	-$75,477
														Subtotal = $345,313

Issue Date FY: 2016 ( Subtotal = $420,000 )
2016	2016	COLD SPRING HARBOR LABORATORY	BUNGTOWN ROAD	COLD SPRING HRBR	NY	11724		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	11/6/2015	NON-COMPETING CONTINUATION	$378,000
2016	2016	COLD SPRING HARBOR LABORATORY	BUNGTOWN ROAD	COLD SPRING HRBR	NY	11724		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	9/2/2016	NON-COMPETING CONTINUATION	$42,000
2016	2016	COLD SPRING HARBOR LABORATORY	BUNGTOWN ROAD	COLD SPRING HRBR	NY	11724		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	2	9/9/2016	NON-COMPETING CONTINUATION	-$97,655
2016	2016	SUNY, STONY BROOK	OFFICE OF RESEARCH SERVICES	STONY BROOK	NY	11794	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	3	9/9/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$97,655
														Subtotal = $420,000

Issue Date FY: 2015 ( Subtotal = $420,000 )
2015	2015	COLD SPRING HARBOR LABORATORY	BUNGTOWN ROAD	COLD SPRING HRBR	NY	11724		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	1/30/2015	NEW	$0
2015	2015	COLD SPRING HARBOR LABORATORY	BUNGTOWN ROAD	COLD SPRING HRBR	NY	11724		USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	1/29/2015	NEW	$420,000
														Subtotal = $420,000

Grand Total All Awards = $1,864,559

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Loss of siRNA based gene silencing and retrotransposon activation in TDP-43 mediated neurodegeneration

Award Number: R01NS091748

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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