Heterotypic amyloid interactions as modulators of selective cellular vulnerability

Active Project Grant Awarded Last action

Award ID
R01AG079234
Recipient
Awarding agency
Obligated
$4,549,267

Award facts

Assistance listing
93.866 Aging Research
Completion date 88% complete
Place of performance
Belgium

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Amyloid aggregates are the defining pathological hallmark of alzheimer's disease (ad), yet the role they play and the therapeutic effect in targeting these aggregates remains controversial. Little is known about the impact of the proteome context in which these proteins reside, or what nucleates their aggregation in specific sites in the brain. Studying the composition of amyloid deposits using proteomic approaches has demonstrated the CO- deposition of many other proteins, however currently there is no straightforward chain-of-events that explains plaque composition. The predicament in which the field currently subsists critically highlights the lack of suitable structural-mechanistic models to understand both the causes and consequences of amyloid aggregation in terms of direct molecular interactions, as well as which specific cellular factors determine pathognomonic disease initiation. In this project, the switch laboratory in VIB flanders institute for biotechnology will approach the selective amyloid aggregation of beta amyloid (ASS) and TAU in ad mechanistically and will do a systematic search for potential interacting partners based on the sequence- and structure-specificity of aggregation. This systematic and proteome-wide screen is based on the assumption that amyloid aggregation is initiated by the specific interaction of aggregation-prone regions (APRS) within ASS and TAU with aggregation-prone sequence segments in other proteins within the background proteome. They have developed a unique computational pipeline to model heterotypic interactions with sufficient predictive power to identify amyloid modifiers in cells. The project will investigate the in vivo impact of heterotypic amyloid interactions in mouse models and for the hits, will analyze in molecular detail how the aggregation of ASS and TAU is modified by the interactions. Aim 1 will run an in-silico screen with special emphasis on known factors related to selective vulnerably. The computational screen will use all-atom modelling of sequence segments with sequence homology to the APRS of ASS and TAU to identify other brain-expressed proteins that may modify the aggregation of ASS or TAU. Aim 2 will screen full-length proteins in cellular models to identify candidates that can modify amyloid aggregation of ASS and TAU in a complex biological context. Aim 3 will identify modifiers that have an effect in vivo by expressing the most potent modifier proteins in mouse models, to study the impact on aggregation onset and extent of amyloid pathology of ASS and TAU. For the most promising modifiers identified in aims 2 and 3, aim 4 will unravel the molecular mechanism of selected heterotypic amyloid interactions use state-of-the-art biophysical methods to elucidate exactly how these interactions change the amyloid formation of ASS and TAU.

Transactions

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Amendment $481,531
Amendment $39,041
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Amendment $439,210
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Amendment $510,259
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Amendment $521,707
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Amendment $523,651
Original award $523,651
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Quick answers

Who received award R01AG079234?

R01AG079234 was awarded to Vlaams Instituut Voor Biotechnologie - Flanders Institute For Biotechnology by National Institute on Aging (National Institutes of Health) on September 30, 2022.

How much is award R01AG079234 worth?

$4,549,267 has been obligated on R01AG079234.

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