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

CD8 T cell mediated disruption of Blood Brain Barrier Tight Junctions

Award Number: R01NS103212
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: 07/01/2017
PERIOD OF PERFORMANCE END DATE: 02/28/2030

Group Awards By:

View Award Description

CD8 T cell mediated disruption of Blood Brain Barrier Tight Junctions - ABSTRACT The most severe clinical complication of Plasmodium falciparum infection is cerebral malaria (CM) which has high morbidity despite treatment. Disruption of the blood-brain barrier (BBB), extensive edema, and brain swelling are associated with fatal human CM. Given the above observations in human CM, the mechanism of BBB disruption and vascular permeability needs to be defined. Plasmodium berghei ANKA (PbA) infection of mice is an established model of human CM. Considerable CNS pathology associated with PbA infection is driven by an acute CD8 T cell response which induces disruption of BBB tight junction proteins and CNS vascular permeability. Our laboratory developed an additional inducible model of CD8 T cell mediated BBB disruption which is initiated through administration of antigenic peptide. This Peptide Induced Fatal Syndrome (PIFS) model shares many similarities to lethal PbA infection in that CD8 T cells use perforin and engage brain vasculature to induce BBB disruption Importantly, we report that CD8 T resident memory (TRM) cells can induce BBB disruption, long after clearance of viral pathogen. We also demonstrate these CD8 TRM can be induced to mediate BBB disruption repeatedly, in multiple insults, at time points months apart. This discovery provides a unique opportunity to study the effects of CD8 TRM cells on brain vascular health and neuropathology in chronic phases of neurologic disease. Both PbA infection and the PIFS model employ a common pathway in which antigen-specific CD8 T cells engage endothelial cells of brain vasculature to promote BBB disruption. This was determined using our novel MHC class I conditional knockout mice generated by my research program. Our central hypothesis is CD8 T resident memory (TRM) cells directly engage brain vasculature in an MHC class I molecule restricted manner, initiating broad immune cell infiltration and BBB disruption. We will test this hypothesis through execution of the following aims: Specific Aim #1 – Identify the anatomical location of antigen-specific acute and memory CD8 T cell activation during onset of BBB disruption Specific Aim #2 – Determine the impact of T cell engagement of endothelial cell expressed MHC class I and MHC class II molecules on immune cell recruitment to brain parenchyma Specific Aim #3 – Define the neuropathological impact of repeated insult by CD8 TRM cell mediated BBB disruption The proposed work is innovative because it capitalizes on our unique transgenic mouse models, collaborations, novel imaging methodology, and core facilities available to our research program at Mayo Clinic. Our goal is to define mechanistically the contribution of inflammation to BBB disruption in neurologic disease using established models. Beyond the innovative methodology employed, the concept that antigen presentation by brain vasculature causes BBB disruption in acute and chronic phases of CNS disease has implications for the role of acute and memory CD8 T cells in complex human neurological conditions in general.


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 = $593,164 )
2026	2026	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	10	2/23/2026	NON-COMPETING CONTINUATION	$593,164
2026	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	1/21/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $593,164

Issue Date FY: 2025 ( Subtotal = $590,800 )
2025	2025	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	5/1/2025	COMPETING CONTINUATION	$590,800
														Subtotal = $590,800

Issue Date FY: 2024 ( Subtotal = $399,756 )
2024	2024	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	5/10/2024	NON-COMPETING CONTINUATION	$399,756
														Subtotal = $399,756

Issue Date FY: 2023 ( Subtotal = $412,120 )
2023	2023	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	7	4/13/2023	NON-COMPETING CONTINUATION	$412,120
														Subtotal = $412,120

Issue Date FY: 2022 ( Subtotal = $412,120 )
2022	2022	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	4/14/2022	NON-COMPETING CONTINUATION	$412,120
														Subtotal = $412,120

Issue Date FY: 2021 ( Subtotal = $412,120 )
2021	2021	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	5	4/12/2021	NON-COMPETING CONTINUATION	$412,120
2021	2020	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	3/31/2021	COMPETING CONTINUATION	$154
2021	2019	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	3/31/2021	SUPPLEMENT FOR EXPANSION	-$154
														Subtotal = $412,120

Issue Date FY: 2020 ( Subtotal = $412,120 )
2020	2020	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	6/19/2020	COMPETING CONTINUATION	$412,120
														Subtotal = $412,120

Issue Date FY: 2019 ( Subtotal = $695,626 )
2019	2019	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	6/10/2019	NON-COMPETING CONTINUATION	$347,813
2019	2019	MAYO CLINIC	200 FIRST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	9/12/2019	SUPPLEMENT FOR EXPANSION	$347,813
														Subtotal = $695,626

Issue Date FY: 2018 ( Subtotal = $347,813 )
2018	2018	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	5/9/2018	NON-COMPETING CONTINUATION	$347,813
														Subtotal = $347,813

Issue Date FY: 2017 ( Subtotal = $347,813 )
2017	2017	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	6/9/2017	NEW	$347,813
														Subtotal = $347,813

Grand Total All Awards = $4,623,452

Top

All Categories

About

Search

Reports

Data Submission

Award Information

CD8 T cell mediated disruption of Blood Brain Barrier Tight Junctions

Award Number: R01NS103212

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: 07/01/2017

PERIOD OF PERFORMANCE END DATE: 02/28/2030

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer