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Dissecting the role of LAMA1 genetic variant in modulating blood-brain barrier integrity and protection against APOE4-driven Alzheimer's disease

Award Number: R21NS149249
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/15/2026
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Dissecting the role of LAMA1 genetic variant in modulating blood-brain barrier integrity and protection against APOE4-driven Alzheimer's disease - PROJECT ABSTRACT Alzheimer’s disease (AD) is marked by progressive cognitive decline and blood-brain barrier (BBB) breakdown, especially in individuals carrying the high-risk APOEε4 genotype. Yet, some APOEε4 homozygotes remain cognitively intact, suggesting the presence of genetic resilience mechanisms. Through whole-genome sequencing of resilient APOEε4 carriers, we identified a rare protective missense variant in LAMA1 (G967D), a key laminin subunit critical for BBB integrity. We hypothesize that this LAMA1 variant modifies extracellular matrix (ECM) composition, mitigating BBB dysfunction. In Aim 1, we will generate the LAMA1 variant in human iPSC- derived astrocyte-endothelial co-cultures within 3D hydrogels and assess ECM remodeling and proteomic changes. In Aim 2, we will use CRISPR-edited APOEε4 zebrafish models to examine the in vivo impact of orthologous LAMA1 genetic variant on BBB dysfunction, vessel leakage, gliosis, and gene expression in BBB cell types. By integrating human and zebrafish models with imaging, single-cell transcriptomics, and proteomics, this project will provide novel mechanistic understanding of LAMA1 genetic variant and its therapeutic potential for maintaining BBB homeostasis in genetically at-risk populations.


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 = $452,375 )
2026	2026	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	6/16/2026	NEW	$452,375
														Subtotal = $452,375

Grand Total All Awards = $452,375

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Dissecting the role of LAMA1 genetic variant in modulating blood-brain barrier integrity and protection against APOE4-driven Alzheimer's disease

Award Number: R21NS149249

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/15/2026

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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