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Innovating Yeast and Human Genetics Approaches to Define Mechanisms of Neurodegenerative Disease

Award Number: R35NS097263
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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Innovating Yeast and Human Genetics Approaches to Define Mechanisms of Neurodegenerative Disease - This is a proposal to combine our three NINDS funded R01 projects into one larger R35 award, enabling us the time and flexibility to explore important biological questions relevant to human neurodegenerative diseases. Over the past eight years, my laboratory has used a combination of yeast and human genetics to define novel mechanisms of ALS, FTD, and Parkinson's disease. These experiments have led to the discovery of ataxin 2 intermediate-length polyglutamine expansions as a major genetic risk factor for ALS, the discovery of RNA lariat debranching enzyme as a powerful therapeutic target for TDP-43 proteinopathies, a new cellular pathway to explain how C9orf72 mutations could cause neurodegeneration and unexpected connections between seemingly distinct Parkinson's disease genes. In preliminary studies, we have found that genetic reduction of ataxin 2 in mouse profoundly extends survival of TDP-43 transgenic mice (>80% increase in lifespan). We propose studies to explore how ataxin 2 protects against TDP-43 proteinopathy, test ataxin 2 in other mouse models (e.g., C9orf72 and FUS/TLS), and to pursue antisense oligonucleotides targeting ataxin 2 in human cell models. While our previous work has stemmed from yeast models and genetic modifier screens, we now propose an ambitious advance – performing genomewide modifier screens in human cells using CRISPR/Cas9 gene activation and inactivation libraries. We have already performed three pilot screens with C9orf72 models and have identified several potent modifiers, which we will validate in primary neurons and mouse models. I plan to take my lab into this new direction by performing CRISPR screens in human cells with TDP-43, FUS, alpha-synuclein, ataxin 2, and further C9orf72 models (e.g., RNA vs. DPRs). We are also interested in the process of RAN (repeat-associated non-ATG) translation, which has emerged as a powerful facet of several nucleotide-repeat diseases (including c9ALS/FTD). We propose experiments to discover the molecular mechanisms of RAN translation in order to design specific inhibitors and we have already identified at least two genes that seem to be required for RAN translation. Together, we present an ambitious research program aimed at defining novel mechanisms of human neurodegenerative diseases and then intensely working to translate those mechanisms to novel therapies to help treat these devastating conditions.


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 = $0 )
2025	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	4/1/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $1,085,210 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	11/14/2023	NON-COMPETING CONTINUATION	$1,006,894
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	8	4/12/2024	NON-COMPETING CONTINUATION	$78,316
														Subtotal = $1,085,210

Issue Date FY: 2023 ( Subtotal = $1,118,773 )
2023	2023	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	12/13/2022	NON-COMPETING CONTINUATION	$1,118,773
														Subtotal = $1,118,773

Issue Date FY: 2022 ( Subtotal = $1,118,773 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	12/3/2021	NON-COMPETING CONTINUATION	$924,544
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	6	3/24/2022	NON-COMPETING CONTINUATION	$102,729
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	2/10/2022	SUPPLEMENT FOR EXPANSION	$91,500
														Subtotal = $1,118,773

Issue Date FY: 2021 ( Subtotal = $1,036,834 )
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	12/15/2020	NON-COMPETING CONTINUATION	$933,149
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	1/26/2021	NON-COMPETING CONTINUATION	$103,685
														Subtotal = $1,036,834

Issue Date FY: 2020 ( Subtotal = $1,132,610 )
2020	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	2/12/2020	NON-COMPETING CONTINUATION	$147,488
2020	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	11/27/2019	NON-COMPETING CONTINUATION	$985,122
														Subtotal = $1,132,610

Issue Date FY: 2019 ( Subtotal = $1,123,049 )
2019	2019	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	11/23/2018	NON-COMPETING CONTINUATION	$1,027,273
2019	2019	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	2/7/2019	SUPPLEMENT FOR EXPANSION	$95,776
														Subtotal = $1,123,049

Issue Date FY: 2018 ( Subtotal = $1,027,273 )
2018	2018	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	4/25/2018	NON-COMPETING CONTINUATION	$102,729
2018	2018	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	11/15/2017	NON-COMPETING CONTINUATION	$924,544
														Subtotal = $1,027,273

Issue Date FY: 2017 ( Subtotal = $939,520 )
2017	2017	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	1/31/2017	NEW	-$6,090
2017	2017	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/25/2016	NEW	$945,610
														Subtotal = $939,520

Grand Total All Awards = $8,582,042

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Innovating Yeast and Human Genetics Approaches to Define Mechanisms of Neurodegenerative Disease

Award Number: R35NS097263

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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