Wednesday, May 1, 2024 5/1/2024

Molecular mechanisms of membrane disruption induced by early-stage aggregation of beta-amyloid peptides

Award Number: R01GM125853
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary Because of the recent failures in the development of anti-amyloid therapeutic strategies for curing Alzheimer's disease (AD), it is prompt to re-evaluate the existing amyloid cascade hypothesis from all possible aspects. Among all these efforts, biophysical and structural characterizations of ß-amyloid aggregates in in- vitro model systems, especially the works that involve the high-resolution solid-state nuclear magnetic resonance (ssNMR) spectroscopy, provide invaluable information from the fundamental sides. However so far, most of these high-resolution works have been focused on the atomic structures of either amyloid fibrils or non- fibrillar aggregates. Very little high-resolution studies have been performed to directly probe the cellular membrane disruption effects induced by the aggregation process of ß-amyloid peptides, which are potentially associated with the neurotoxicity mechanisms of the ß-amyloid aggregates. A major challenge that prevented the high-resolution studies of ß-amyloid-peptide-induced membrane disruption effects in model systems was the heterogeneity, which usually involved co-existence of multiple membrane disruption pathways with mixed intermediate structures. This proposal attempts to solve this problem by generating model systems with distinct predominant membrane disruption effects. These model systems, which contain different ß amyloid aggregates and phospholipid liposomes, are characterized by distinct time-dependent membrane disruption features and structurally homogeneous endpoints. Therefore, they can be studied individually in terms of their membrane disruption effects using high-resolution ssNMR approaches. The outcomes of this proposal, if successful, will provide crucial insights on the high-resolution molecular interactions between ß amyloid aggregates and membranes that are responsible to the membrane disruption. These information help to explain the neuronal cellular toxicity of ß-amyloid aggregates, which further contribute to the re-evaluation of amyloid cascade hypothesis.


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	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	4400 VESTAL PKWY E	BINGHAMTON	NY	13902	BROOME	USA	Biomedical Research and Research Training	000	5	12/13/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $276,480 )
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	4400 VESTAL PKWY E	BINGHAMTON	NY	13902	BROOME	USA	Biomedical Research and Research Training	000	5	12/22/2021	NON-COMPETING CONTINUATION	$248,832
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	4400 VESTAL PKWY E	BINGHAMTON	NY	13902	BROOME	USA	Biomedical Research and Research Training	001	5	6/27/2022	NON-COMPETING CONTINUATION	$27,648
														Subtotal = $276,480

Issue Date FY: 2021 ( Subtotal = $274,818 )
2021	2021	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	4400 VESTAL PKWY E	BINGHAMTON	NY	13902	BROOME	USA	Biomedical Research and Research Training	000	4	12/17/2020	NON-COMPETING CONTINUATION	$247,336
2021	2021	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	4400 VESTAL PKWY E	BINGHAMTON	NY	13902	BROOME	USA	Biomedical Research and Research Training	001	4	3/1/2021	NON-COMPETING CONTINUATION	$27,482
														Subtotal = $274,818

Issue Date FY: 2020 ( Subtotal = $330,777 )
2020	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	4400 VESTAL PKWY E	BINGHAMTON	NY	13902	BROOME	USA	Biomedical Research and Research Training	002	3	7/20/2020	SUPPLEMENT FOR EXPANSION	$56,712
2020	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	4400 VESTAL PKWY E	BINGHAMTON	NY	13902	BROOME	USA	Biomedical Research and Research Training	001	3	3/11/2020	NON-COMPETING CONTINUATION	$27,407
2020	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	4400 VESTAL PKWY E	BINGHAMTON	NY	13902	BROOME	USA	Biomedical Research and Research Training	000	3	12/17/2019	NON-COMPETING CONTINUATION	$246,658
														Subtotal = $330,777

Issue Date FY: 2019 ( Subtotal = $294,466 )
2019	2019	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	4400 VESTAL PKWY E	BINGHAMTON	NY	13902	BROOME	USA	Biomedical Research and Research Training	001	2	8/27/2019	SUPPLEMENT FOR EXPANSION	$46,514
2019	2019	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	4400 VESTAL PKWY E	BINGHAMTON	NY	13902	BROOME	USA	Biomedical Research and Research Training	000	2	12/24/2018	NON-COMPETING CONTINUATION	$247,952
														Subtotal = $294,466

Issue Date FY: 2018 ( Subtotal = $254,712 )
2018	2018	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	4400 VESTAL PKWY E	BINGHAMTON	NY	13902	BROOME	USA	Biomedical Research and Research Training	000	1	12/22/2017	NEW	$254,712
														Subtotal = $254,712

Grand Total All Awards = $1,431,253

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Molecular mechanisms of membrane disruption induced by early-stage aggregation of beta-amyloid peptides

Award Number: R01GM125853

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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