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Investigating the Role of ZEB1 in Alzheimer's Disease

Award Number: R01AG093685
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2031

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Investigating the Role of ZEB1 in Alzheimer's Disease - Project Summary/Abstract Alzheimer’s disease (AD) is a complex neurodegenerative disease associated with accumulation of β-amyloid (Aβ) and tau aggregates in the brain. These protein aggregates promote inflammation and activation of ER stress signaling pathways that contribute to disease progression. Reduction of amyloid alone can only slow cognitive decline and many patients are ineligible for this treatment. Therefore, new therapies that target downstream signaling pathways are needed that could function either independently or synergistically with anti-amyloid therapies to halt disease progression. We recently identified the transcription factor (TF) ZEB1 as a driver of neuronal responses to AD pathologies in a single cell multiomics analysis of human post-mortem tissues. Transcription factors can integrate multiple ER stress signaling inputs to elicit distinct cellular responses in AD. We hypothesize that ER stress signaling regulates ZEB1 function through protein-protein interactions and post- translational modifications to modulate cell type-specific target gene expression in response to AD pathologies. In this proposal, we will utilize human post-mortem cortical tissues, matched patient-derived induced pluripotent stem cells (iPSC) and genetic iPSC models of sporadic and familial AD to define the cell type-specific mechanisms of ZEB1 activation in neurons and determine the impact of TF activity on AD-associated molecular phenotypes. These data will provide a clear understanding how ZEB1 regulates the cell type-specific responses to ER stress due to AD pathology in neurons. Importantly, this study will initiate a new avenue of research in targeting ZEB1 and its downstream effectors to attenuate cellular responses leading to neurodegeneration.


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: 2026 ( Subtotal = $696,614 )
2026	2026	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Aging Research	000	1	8/25/2026	NEW	$696,614
														Subtotal = $696,614

Grand Total All Awards = $696,614

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Investigating the Role of ZEB1 in Alzheimer's Disease

Award Number: R01AG093685

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2031

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