Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Drugs repositioning to target TREM2 in Alzheimer disease

Award Number: R01AG081228
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/15/2023
PERIOD OF PERFORMANCE END DATE: 02/29/2028

Group Awards By:

View Award Description

Drugs repositioning to target TREM2 in Alzheimer disease - Single amino acid variants in TREM2 have been identified by genome-wide association studies to be one of the strongest genetic risk factors for late-onset Alzheimer's disease (AD). AD-associated variants in TREM2 impair TREM2's ability to bind and signal in response to ligands in the body, further affecting TREM2-mediated immune activation in AD. Identifying the available drugs as TREM2 ligands and understanding how the drugs regulate TREM2-mediated immune activation, could reposition the available drugs to target TREM2 and aid the development of combined drug therapy for AD treatment. The central hypothesis of the proposed study is that the available drugs, including FDA-approved drugs, could bind TREM2 at either basic and/or hydrophobic binding site, allosteric effect of drugs at TREM2 either or two binding sites could regulate ligand binding at both sites to modulate TREM2-mediated immune activation in AD, and compensate for the loss of TREM2-mediated immune activities by AD-associated TREM2 variants. We will test the hypothesis with three Aims with integrated computational and experimental approaches. Aim 1 is to identify available drugs bound basic or/and hydrophobic binding sites on TREM2 with unbiased virtual screening and biophysical and biological experimental validation. Aim 2 is to characterize the interactions of the available drugs with TREM2 and determine the allosteric effect of available drugs binding at basic and hydrophobic TREM2 binding sites, and on TREM2-mediated immune activation. Aim 3 is to determine whether the available drugs bound TREM2 could counteract the loss of TREM2-ApoE binding and its mediated immune activities caused by AD- associated TREM2 variants. New knowledge gained from this study could have high impact for AD research and treatment by repositioning the available drugs to target TREM2 and further the insight into available drugs modulating TREM2-mediated immune activation, offering a molecular basis for strategy development of using available drugs including drug combinations to target TREM2 for AD treatment. Investigating novel TREM2 functional mechanism in AD at a fundamental level  how TREM2 activation by available drugs at basic and/or hydrophobic sites and whether and how available drugs compensate for the loss of TREM2 immune activity by AD-associated variants  is the necessary first step. Innovations of study include: 1) This will be the first study to identify available drugs as TREM2 ligand by targeting both TREM2 basic and hydrophobic sites in a more conclusive manner with unbiased virtual screening and validation with biophysical binding and biological cellular function experiments. 2) Results from this study will unveil novel findings about the allosteric effects of available drugs binding at either TREM2 binding site, on TREM2 binding AD pathology related ligand in the body including ApoE, and on TREM2-mediated immune activation. 3) Research outcomes could propose targeting TREM2 with available drugs currently used for other conditions to compensate for loss of TREM2-mediated immune activities by AD-associated variants for AD treatment.


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 = $564,154 )
2026	2026	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Aging Research	000	4	3/4/2026	NON-COMPETING CONTINUATION	$564,154
														Subtotal = $564,154

Issue Date FY: 2025 ( Subtotal = $564,646 )
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Aging Research	001	3	6/9/2025	NON-COMPETING CONTINUATION	$46,094
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Aging Research	000	3	3/7/2025	NON-COMPETING CONTINUATION	$518,552
														Subtotal = $564,646

Issue Date FY: 2024 ( Subtotal = $587,814 )
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Aging Research	001	2	6/28/2024	NON-COMPETING CONTINUATION	$58,782
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Aging Research	000	2	2/13/2024	NON-COMPETING CONTINUATION	$529,032
														Subtotal = $587,814

Issue Date FY: 2023 ( Subtotal = $611,134 )
2023	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Aging Research	000	1	6/14/2023	NEW	$611,134
														Subtotal = $611,134

Grand Total All Awards = $2,327,748

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Drugs repositioning to target TREM2 in Alzheimer disease

Award Number: R01AG081228

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/15/2023

PERIOD OF PERFORMANCE END DATE: 02/29/2028

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer