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Mechanisms of Prion Protein Toxicity

Award Number: R01NS065244
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: 07/01/2010
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Mechanisms of Prion Protein Toxicity - The overall goal of this application is to understand the mechanisms by which prions cause damage to synapses, and establish and maintain a self-propagating infection in the CNS. We also wish to develop pharmacologic therapies for these disorders based on our knowledge of the molecular and cellular mechanisms underlying the disease process. Although the molecular templating model for prion propagation, in which PrPC is converted into infectious PrPSc, is now widely accepted, the mechanisms by which prions actually cause neurodegeneration have remained mysterious. There is now considerable evidence that cell- surface PrPC mediates many of the neurotoxic effects of PrPSc, likely by serving as a receptor that binds PrPSc during the first step of the prion conversion process. However, how this initiates downstream toxic signals in the cytoplasm, and how these signals alter synaptic structure or function were largely unknown. The work we have accomplished during the previous grant cycle has provided key insights into this issue by defining a PrPC/NMDAR/p38 MAPK signaling pathway that mediates the earliest effects of PrPSc synaptotoxicity. Based on a combination of structural analysis and functional assays, we have proposed a model in which the N-terminal domain of PrPC serves as a toxic effector that is regulated by specific docking interactions with the C-terminal domain. Artificial disruption of this intramolecular interaction results in a variety of toxic activities in cellular and transgenic models. In this renewal application, we propose, first, to elucidate how prion synaptotoxic signaling is initiated at the cell surface. Second, we plan to dissect the intracellular signaling cascades that are activated by prions, and how they result in synaptic dysfunction. Third, we will investigate the mechanisms by which cells establish and maintain prion infection. We anticipate that the studies proposed here will provide powerful insights into biological mechanisms that are common to multiple neurodegenerative disorders caused by toxic protein aggregates in the brain, and will lead to the discovery of shared therapeutic approaches that can be used to treat them.


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 = $768,128 )
2025	2025	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	15	6/6/2025	NON-COMPETING CONTINUATION	$768,128
														Subtotal = $768,128

Issue Date FY: 2024 ( Subtotal = $781,315 )
2024	2024	TRUSTEES OF BOSTON UNIVERSITY	85 EAST NEWTON ST # M-921	BOSTON	MA	02118	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	14	6/28/2024	NON-COMPETING CONTINUATION	$781,315
														Subtotal = $781,315

Issue Date FY: 2023 ( Subtotal = $782,968 )
2023	2023	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	13	6/12/2023	NON-COMPETING CONTINUATION	$782,968
														Subtotal = $782,968

Issue Date FY: 2022 ( Subtotal = $784,573 )
2022	2022	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	12	7/14/2022	NON-COMPETING CONTINUATION	$784,573
2022	2020	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	11/29/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $784,573

Issue Date FY: 2021 ( Subtotal = $786,131 )
2021	2021	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	11	6/22/2021	COMPETING CONTINUATION	$648,557
2021	2021	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	11	9/23/2021	COMPETING CONTINUATION	$137,574
2021	2020	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	6/14/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $786,131

Issue Date FY: 2020 ( Subtotal = $634,826 )
2020	2020	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	2/11/2020	NON-COMPETING CONTINUATION	$634,826
														Subtotal = $634,826

Issue Date FY: 2019 ( Subtotal = $636,850 )
2019	2019	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	12/28/2018	NON-COMPETING CONTINUATION	$636,850
														Subtotal = $636,850

Issue Date FY: 2018 ( Subtotal = $638,244 )
2018	2018	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	12/13/2017	NON-COMPETING CONTINUATION	$574,419
2018	2018	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	8	5/8/2018	NON-COMPETING CONTINUATION	$63,825
														Subtotal = $638,244

Issue Date FY: 2017 ( Subtotal = $639,007 )
2017	2017	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	12/23/2016	NON-COMPETING CONTINUATION	$575,106
2017	2017	TRUSTEES OF BOSTON UNIVERSITY	85 E NEWTON ST M-921	BOSTON	MA	02118	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	7	6/9/2017	NON-COMPETING CONTINUATION	$63,901
														Subtotal = $639,007

Issue Date FY: 2016 ( Subtotal = $655,922 )
2016	2016	BOSTON UNIVERSITY	25 BUICK ST	BOSTON	MA	02215	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	6	9/23/2016	COMPETING CONTINUATION	$111,977
2016	2016	BOSTON UNIVERSITY	25 BUICK ST	BOSTON	MA	02215	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	2/23/2016	COMPETING CONTINUATION	$543,945
2016	2014	BOSTON UNIVERSITY	25 BUICK STREET	BOSTON	MA	02215	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	2/22/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $655,922

Issue Date FY: 2014 ( Subtotal = $347,422 )
2014	2014	BOSTON UNIVERSITY	25 BUICK ST	BOSTON	MA	02215	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	6/10/2014	NON-COMPETING CONTINUATION	$347,422
														Subtotal = $347,422

Issue Date FY: 2013 ( Subtotal = $338,649 )
2013	2013	BOSTON UNIVERSITY	25 BUICK ST	BOSTON	MA	02215	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	6/12/2013	NON-COMPETING CONTINUATION	$338,649
														Subtotal = $338,649

Issue Date FY: 2012 ( Subtotal = $350,932 )
2012	2012	BOSTON UNIVERSITY	25 BUICK ST	BOSTON	MA	02215	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	8/31/2012	NON-COMPETING CONTINUATION	$350,932
														Subtotal = $350,932

Issue Date FY: 2011 ( Subtotal = $357,603 )
2011	2011	BOSTON UNIVERSITY	25 BUICK ST	BOSTON	MA	02215	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	2	7/27/2011	NON-COMPETING CONTINUATION	$3,525
2011	2011	BOSTON UNIVERSITY	25 BUICK ST	BOSTON	MA	02215	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	7/5/2011	SUPPLEMENT FOR EXPANSION	$3,575
2011	2011	BOSTON UNIVERSITY	25 BUICK ST	BOSTON	MA	02215	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	6/15/2011	NON-COMPETING CONTINUATION	$350,503
														Subtotal = $357,603

Issue Date FY: 2010 ( Subtotal = $350,160 )
2010	2010	BOSTON UNIVERSITY	25 BUICK ST	BOSTON	MA	02215	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	6/18/2010	NEW	$350,160
														Subtotal = $350,160

Grand Total All Awards = $8,852,730

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Mechanisms of Prion Protein Toxicity

Award Number: R01NS065244

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: 07/01/2010

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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