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The Role of Pericytes in the Vascular Dysfunction of Sepsis

Award Number: R35GM149203
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2023
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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The Role of Pericytes in the Vascular Dysfunction of Sepsis - Project Summary: Sepsis affects more than 19 million people each year. With improved treatment strategies, more and more patients survive sepsis. The majority of these survivors develop cognitive impairment and mental health problems. However, the mechanisms that promote sepsis-associated encephalopathies (SAE) remain largely unknown, and there is a lack of SAE-targeted treatments. The long-term goals of our research program are to understand the mechanisms that lead to cerebrovascular dysfunction and cognitive impairment post sepsis and to develop novel targeted treatments for sepsis-induced cognitive impairment. To reach this goal, we characterized sepsis-induced cognitive impairment using animal models. We observed that mice exhibit hippocampus-dependent memory impairment associated with pathological neuron dysfunction. To understand the mechanisms behind cognitive impairment post sepsis, we focused on specialized cells in the brain called pericytes, which play a major role in regulating cerebral blood flow and maintaining blood brain barrier integrity. Pericytes form part of the neurovascular unit to meet the energy demands of the brain and facilitate neuro- inflammatory responses. However, the role of pericytes in sepsis-induced cognitive impairment remains unknown. Our studies demonstrated that the transcription factor friend leukemia virus integration 1 (Fli-1) regulates pericyte activation and viability. We also observed that brain pericyte numbers decreased after sepsis and that pericytes underwent apoptosis after their initial activation and production of inflammatory mediators. Pericyte loss resulted in vascular leakage and recruitment of inflammatory monocytes. We reported previously that Fli-1 governs pericyte viability through regulating caspase 1/3 expression. In our preliminary studies, we demonstrated that pericyte Fli-1 knockout mice exhibit decreased inflammatory mediator production in response to LPS. More importantly, we demonstrated that Fli-1 levels were higher in the hippocampus regions of post- mortem brain tissue from septic patients compared to controls. In this R35/MIRA application, we propose to use newly developed, unbiased approaches such as single nucleus RNA sequencing and imaging mass cytometry alongside inducible pericyte-specific Fli-1 knockout mice generated in our laboratory and novel antisense oligonucleotide Gapmers targeting Fli-1 recently developed by our group to understand the role of pericytes in vascular dysfunction and cognitive impairment post sepsis. The successful completion of the proposed studies will lead to better understanding of the mechanisms of vascular cognitive impairment post sepsis and the development of novel SAE-targeted treatments.


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 = $377,539 )
2026	2026	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Biomedical Research and Research Training	000	4	4/2/2026	NON-COMPETING CONTINUATION	$377,539
														Subtotal = $377,539

Issue Date FY: 2025 ( Subtotal = $377,539 )
2025	2025	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Biomedical Research and Research Training	001	3	4/4/2025	NON-COMPETING CONTINUATION	$377,539
2025	2024	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Biomedical Research and Research Training	000	2	11/5/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $377,539

Issue Date FY: 2024 ( Subtotal = $626,737 )
2024	2024	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Biomedical Research and Research Training	001	2	5/21/2024	NON-COMPETING CONTINUATION	$37,753
2024	2024	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Biomedical Research and Research Training	002	2	8/30/2024	SUPPLEMENT FOR EXPANSION	$249,198
2024	2024	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Biomedical Research and Research Training	000	2	3/14/2024	NON-COMPETING CONTINUATION	$339,786
														Subtotal = $626,737

Issue Date FY: 2023 ( Subtotal = $377,539 )
2023	2023	MEDICAL UNIVERSITY OF SOUTH CAROLINA THE	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Biomedical Research and Research Training	000	1	4/19/2023	NEW	$377,539
														Subtotal = $377,539

Grand Total All Awards = $1,759,354

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The Role of Pericytes in the Vascular Dysfunction of Sepsis

Award Number: R35GM149203

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2023

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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