Tuesday, July 1, 2025 7/1/2025

Functional dissection of fibronectin type 3 domains of SORL1 in Alzheimers disease associated microglia

Award Number: R01AG070118
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/15/2021
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Functional dissection of fibronectin type 3 domains of SORL1 in Alzheimers disease associated microglia - Functional dissection of fibronectin type 3 domains of SORL1 in Alzheimer's disease associated microglia Alzheimer's disease (AD) is a multifactorial, complex disease and a leading cause of dementia among aged people. There are no effective pharmacotherapeutic options for prevention and treatment of AD due to lack of complete understanding of disease mechanisms. Interestingly, Genome wide association studies have established that the majority of AD associated loci are found in or near genes that are highly/uniquely expressed in microglia (resident macrophage cells of brain) suggesting the critical role of these cells in disease progression. SORL1 is genetically implicated in late and early onset forms of AD. Studies on postmortem brain tissues have shown reduced levels of SORL1 in AD patient brains. Although, among brain cells microglia show highest expression of SORL1, yet little is known how this protein regulates microglia phenotypes during health and disease. Our preliminary data suggest, that a specific isoform of SORL1 is enriched in microglia and it physically interact through its FN3 domain with WAVE regulator complex (WRC). WRC is emerging as critical regulator of cell migration and phagocytic response hence can serve as therapeutic target for tuning up phenotypes of AD related microglia. In this application, we propose to: (1) determine the molecular mechanism by which SORL1 regulate microglia functions e.g. phagocytosis, chemotaxis, and cytokine expression; (2) Measure SORL- FN3 abundance in AD and non-AD brain microglia from cohorts of deeply characterized individuals (ROSMAP) to establish the relationship among FN3 abundance vs. AD related traits; (3) Identify therapeutic targets within SORL1-WRC using our newly developed CRISPR-mediated saturating mutagenesis approach. Overall, by leveraging innovative CRISPR-Cas9 genome editing technologies (1 & 3) and novel SRM (selected reaction monitoring) based quantitative proteomics and genetics (2) this proposal will accelerate the transition of genetic discoveries to molecular mechanism that can open new avenues for novel therapeutics for 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 = $424,649 )
2025	2025	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Aging Research	000	5	3/6/2025	NON-COMPETING CONTINUATION	$424,649
														Subtotal = $424,649

Issue Date FY: 2024 ( Subtotal = $470,212 )
2024	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Aging Research	001	4	7/3/2024	NON-COMPETING CONTINUATION	$47,021
2024	2024	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Aging Research	000	4	2/22/2024	NON-COMPETING CONTINUATION	$423,191
														Subtotal = $470,212

Issue Date FY: 2023 ( Subtotal = $482,708 )
2023	2023	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Aging Research	000	3	2/15/2023	NON-COMPETING CONTINUATION	$482,708
														Subtotal = $482,708

Issue Date FY: 2022 ( Subtotal = $485,688 )
2022	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Aging Research	000	2	2/7/2022	NON-COMPETING CONTINUATION	$437,117
2022	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Aging Research	001	2	6/13/2022	NON-COMPETING CONTINUATION	$48,571
														Subtotal = $485,688

Issue Date FY: 2021 ( Subtotal = $489,509 )
2021	2021	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	630 W 168TH ST FL 4	NEW YORK	NY	10032	NEW YORK	USA	Aging Research	000	1	3/4/2021	NEW	$489,509
														Subtotal = $489,509

Grand Total All Awards = $2,352,766

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Functional dissection of fibronectin type 3 domains of SORL1 in Alzheimers disease associated microglia

Award Number: R01AG070118

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/15/2021

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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