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

Ifi27l2a as a therapeutic target for stroke

Award Number: R01NS133324
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: 07/15/2023
PERIOD OF PERFORMANCE END DATE: 04/30/2028

Group Awards By:

View Award Description

Ifi27l2a as a therapeutic target for stroke - Abstract Microglia (MG), the resident innate immune cells of the brain, play a critical role in the inflammatory response to stroke. Stroke predominantly affects older individuals. Unfortunately, with aging, MG become increasingly dysfunctional and, in conjunction with other cell types in the brain, contribute to worse outcome following stroke. However, the role of MG in the stroke brain is not exclusively bad, as MG also contribute to repair and recovery following stroke. Thus, the selective regulation of the MG inflammatory response at specific times in the aged brain could be of great therapeutic value for stroke patients. Using single-cell transcriptomic analysis (scRNAseq), we discovered a gene (interferon alpha-inducible protein 27-like protein 2A; Ifi27l2a) that was selectively and highly upregulated in aged MG and further upregulated in MG following stroke. Our initial analysis showed a positive correlation between Ifi27l2a expression and specific sets of pro-inflammatory cytokine and senescence-related genes. These and other studies suggested that Ifi27l2a might play a critical regulatory role in promoting the inflammatory response of MG in the post-stroke brain of mice. Analysis of human brain samples also showed increased expression of IFI27L2 (human isoform) in stroke brain, enhancing the translational relevance of our findings. Next, to define the functional role of Ifi27l2a, we performed a combination of in vitro and in vivo studies, which established a compelling causative role of Ifi27l2a in promoting MG proinflammatory function and in worsening stroke injury. We also established the potential for Ifi27l2a overexpression to induce matrix metalloproteinase (MMP) expression/activity and reactive oxygen species (ROS) production, which are two driving factors in blood brain barrier (BBB) disruption. Finally, using a mouse stroke model, we showed that partial deletion of Ifi27l2a (Ifi27l2a+/- mice) led to significantly improved outcome, as evidenced by reduced infarct volume and reduced microglial activation. Together, these data provide the first direct evidence for Ifi27l2a in modulating MG functionality and brain injury following stroke and establish Ifi27l2a-dependent signaling as a new therapeutic target. Our proposed aims will test the overall hypothesis that increased MG Ifi27l2a contributes to an exaggerated inflammatory response to ischemic stroke in the aged brain and that reducing MG Ifi27l2a expression can attenuate neuroinflammation, reduce BBB disruption, and improve outcome following stroke. If successful, these studies will lay the foundation for a novel strategy based on the selective attenuation of MG pro-inflammatory signaling in the treatment of stroke or other pathologies associated with neuroinflammation.


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 = $500,372 )
2026	2026	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	5/1/2026	NON-COMPETING CONTINUATION	$500,372
														Subtotal = $500,372

Issue Date FY: 2025 ( Subtotal = $500,372 )
2025	2025	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	5/6/2025	NON-COMPETING CONTINUATION	$500,372
														Subtotal = $500,372

Issue Date FY: 2024 ( Subtotal = $446,035 )
2024	2024	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	5/2/2024	NON-COMPETING CONTINUATION	$446,035
														Subtotal = $446,035

Issue Date FY: 2023 ( Subtotal = $459,830 )
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	7/12/2023	NEW	$459,830
														Subtotal = $459,830

Grand Total All Awards = $1,906,609

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Ifi27l2a as a therapeutic target for stroke

Award Number: R01NS133324

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: 07/15/2023

PERIOD OF PERFORMANCE END DATE: 04/30/2028

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer