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Chaperome networks in Alzheimer's disease

Award Number: R01AG067598
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/15/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Chaperome networks in Alzheimer's disease - ABSTRACT The goal of the proposed project is to address how neuronal stress triggered by amyloid-beta and tau oligomeric species induces protein connectivity dysfunctions and alters protein-to-neuronal circuit-to-organ level function. Our focus in on synaptic dysfunction and cognitive deficits in Alzheimer's disease (AD). The hypothesis behind our investigation is that upon entry, the molecular stress triggered by amyloid-beta and tau oligomeric species induces a maladaptive rewiring in the connectivity, and in turn the function of large subsets of downstream neuronal proteins and their networks, through pathologic chaperome scaffolds termed epichaperomes. This hypothesis is supported by preliminary data obtained by the Chiosis lab showing that neuronal lineages are especially prone to form epichaperomes following stressors, and that most vulnerable to epichaperomes are protein pathways with key roles in synaptic plasticity. Additional preliminary experiments supporting feasibility of our experimental plan are provided by studies from the Arancio laboratory and others demonstrating that A and tau oligomers alter synaptic connectivity leading to memory loss. Our preliminary observation that dismantling the pathologic epichaperome structures into normal, folding chaperones rebalances protein network connectivity and functionality to those seen in physiological conditions, are also in support of our scientific premise. To execute these studies, we use iPSC-derived cellular models and mouse models of AD and combine the synergistic expertise of Drs. Arancio (synaptic plasticity, biology of AD), Chiosis (chemical biology of pathologic protein networks, translational research), Fraser (mouse models of AD and AD biology), Zhou (iPSC models in disease) and Mertens (consultant on hiPSC and iN-based cellular models for synaptic function study in AD). We expect that our studies will deliver proteome-wide functional insights and comprehensive, mechanistic understanding into how A and tau oligomers lead to synaptic failure and cognitive defects. In addition to providing new insights into AD biology, our studies have immediate translational applications. With an epichaperome therapeutic discovered by the Chiosis lab moving into Phase 2 clinical evaluation in AD, hypotheses tested within the present proposal may have immediate impact in human AD.


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 = $1,033,893 )
2025	2025	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Aging Research	000	5	1/23/2025	NON-COMPETING CONTINUATION	$1,033,893
														Subtotal = $1,033,893

Issue Date FY: 2024 ( Subtotal = $1,165,073 )
2024	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Aging Research	001	4	6/10/2024	NON-COMPETING CONTINUATION	$116,507
2024	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Aging Research	000	4	1/17/2024	NON-COMPETING CONTINUATION	$1,048,566
														Subtotal = $1,165,073

Issue Date FY: 2023 ( Subtotal = $1,183,214 )
2023	2023	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Aging Research	000	3	1/26/2023	NON-COMPETING CONTINUATION	$1,183,214
														Subtotal = $1,183,214

Issue Date FY: 2022 ( Subtotal = $1,199,524 )
2022	2022	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Aging Research	000	2	4/25/2022	NON-COMPETING CONTINUATION	$1,199,524
														Subtotal = $1,199,524

Issue Date FY: 2021 ( Subtotal = $1,253,488 )
2021	2021	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Aging Research	000	1	2/12/2021	NEW	$1,253,488
														Subtotal = $1,253,488

Grand Total All Awards = $5,835,192

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Chaperome networks in Alzheimer's disease

Award Number: R01AG067598

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/15/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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