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Probing the roles of membrane and cholesterol on Aβ biogenesis and prion protein interactions

Award Number: R01GM107703
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2015
PERIOD OF PERFORMANCE END DATE: 02/29/2024

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Probing the roles of membrane and cholesterol on Aβ biogenesis and prion protein interactions - Project Summary Aggregation of proteins of known sequence is linked to a variety of neurodegenerative disorders. Familial mutations in the Amyloid Precursor Protein (APP), from which the amyloid β (Aβ) protein is derived, have been linked with the early onset of Alzheimer's disease (AD). After fifteen years of fundamental research using computer simulations guided by experiments to identify the factors that determine in vitro aggregation of Aβ, the stage is now set to address questions of utmost relevance to AD. They arise in the context of how heterogeneous membrane environments, cholesterol, and downstream interactions with cofactors affect the cleavage of APP, the production of Aβ, and subsequent interactions of Aβ oligomers and receptors mediating their toxic effects. We are uniquely poised to use computational models to answer these questions and drive advances in critical areas of AD research. In this computational and theoretical research proposal, augmented by synergistic experimental research collaborations, we address fundamental biophysical questions with substantial practical implications articulated in three specific aims. (1) Developing a quantitative understanding of how membrane lipid composition and structural heterogeneity impacts the partitioning of APP and secretases critical to the processing of APP in the genesis Aβ. (2) Elucidating the crucial role cholesterol plays in determining the extent of amyloidogenic cleavage in the differential processing of APP. (3) Characterizing at the molecular-level the conformational transitions and interactions involved in the binding of Aβ monomer and oligomers to cellular prion protein (PrPC), implicated in a plausible mechanism of Aβ cytotoxicity. The proposed coordinated studies will lead to a fundamental molecular-level understanding of the network of interactions that are essential to the biogenesis of Aβ protein and its role as a pathogenic agent in AD. Through the development of novel computational models and identification of new concepts, the expected outcomes could change the landscape for the use of simulations and theory not only in the AD field but also in the general study of membrane- protein interactions.!


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 = $0 )
2024	2022	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Biomedical Research and Research Training	000	8	8/26/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $379,383 )
2022	2022	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Biomedical Research and Research Training	001	8	5/17/2022	NON-COMPETING CONTINUATION	$37,939
2022	2022	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Biomedical Research and Research Training	000	8	2/28/2022	NON-COMPETING CONTINUATION	$341,444
														Subtotal = $379,383

Issue Date FY: 2021 ( Subtotal = $379,383 )
2021	2021	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Biomedical Research and Research Training	000	7	3/29/2021	NON-COMPETING CONTINUATION	$379,383
2021	2019	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Biomedical Research and Research Training	004	5	4/14/2021	COMPETING CONTINUATION	$50,013
2021	2019	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Biomedical Research and Research Training	002	5	4/2/2021	COMPETING CONTINUATION	-$34,605
2021	2018	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Biomedical Research and Research Training	001	4	4/2/2021	NON-COMPETING CONTINUATION	$34,605
2021	2018	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Biomedical Research and Research Training	003	4	4/14/2021	NON-COMPETING CONTINUATION	-$50,013
														Subtotal = $379,383

Issue Date FY: 2020 ( Subtotal = $379,383 )
2020	2020	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Biomedical Research and Research Training	002	6	2/19/2020	NON-COMPETING CONTINUATION	$379,383
2020	2019	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Biomedical Research and Research Training	001	5	12/5/2019	COMPETING CONTINUATION	$34,605
2020	2018	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Biomedical Research and Research Training	000	4	12/5/2019	NON-COMPETING CONTINUATION	-$34,605
														Subtotal = $379,383

Issue Date FY: 2019 ( Subtotal = $395,633 )
2019	2019	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Biomedical Research and Research Training	001	5	5/7/2019	COMPETING CONTINUATION	$395,633
2019	2018	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Biomedical Research and Research Training	000	4	5/6/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $395,633

Issue Date FY: 2018 ( Subtotal = $295,956 )
2018	2018	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Biomedical Research and Research Training	001	4	5/15/2018	NON-COMPETING CONTINUATION	$29,597
2018	2018	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Biomedical Research and Research Training	000	4	2/13/2018	NON-COMPETING CONTINUATION	$266,359
														Subtotal = $295,956

Issue Date FY: 2017 ( Subtotal = $295,956 )
2017	2017	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Biomedical Research and Research Training	001	3	6/20/2017	NON-COMPETING CONTINUATION	$29,597
2017	2017	TRUSTEES OF BOSTON UNIVERSITY	1 SILBER WAY	BOSTON	MA	02215	SUFFOLK	USA	Biomedical Research and Research Training	000	3	2/24/2017	NON-COMPETING CONTINUATION	$266,359
														Subtotal = $295,956

Issue Date FY: 2016 ( Subtotal = $295,956 )
2016	2016	BOSTON UNIVERSITY	25 BUICK ST	BOSTON	MA	02215	SUFFOLK	USA	Biomedical Research and Research Training	000	2	2/9/2016	NON-COMPETING CONTINUATION	$295,956
														Subtotal = $295,956

Issue Date FY: 2015 ( Subtotal = $311,881 )
2015	2015	BOSTON UNIVERSITY	25 BUICK ST	BOSTON	MA	02215	SUFFOLK	USA	Biomedical Research and Research Training	000	1	2/27/2015	NEW	$311,881
														Subtotal = $311,881

Grand Total All Awards = $2,733,531

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Probing the roles of membrane and cholesterol on Aβ biogenesis and prion protein interactions

Award Number: R01GM107703

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2015

PERIOD OF PERFORMANCE END DATE: 02/29/2024

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