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Principal Investigator: Hongkuan Fan
Organization: MEDICAL UNIVERSITY OF SOUTH CAROLINA
Fiscal Year: 2024
Award: $377,539
Funding agency: National Institute of General Medical Sciences
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.
Terms: <Adventitial Cell><Affect><Ammon Horn><Animal Model><Animal Models and Related Studies><Antisense Agent><Antisense Oligonucleotides><Apoptosis><Apoptosis Pathway><Apoptosis-Related Cysteine Protease Caspase 1><Autopsy><Blood - brain barrier anatomy><Blood Vessels><Blood monocyte><Blood-Brain Barrier><Brain><Brain Nervous System><Brain Vascular Disorders><CASP-1><CASP1><CASP1 gene><Caspase-1><Caspase-1 Gene><Cell Body><Cells><Cerebral vascular pericyte><Cerebrovascular Circulation><Cerebrovascular Disease><Cerebrovascular Disorders><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Cornu Ammonis><Cytometry><Development><Disturbance in cognition><ERGB Transcription Factor><EWSR2><Encephalon><Encephalopathies><Ewing Sarcoma Breakpoint Region 2><Exhibits><Extravasation><FLI1><FLI1 Protein><FLI1 Transcription Factor><FLI1 gene><Fli-1 proto-oncogene, ETS transcription factor><Friend Leukemia Virus Integration 1 Protein><Friend Leukemia Virus Integration 1 Transcription Factor><Friend leukemia virus integration 1><Goals><Hemato-Encephalic Barrier><Hippocampus><ICE Protease><IL-1 beta Convertase><IL-1 beta-Converting Enzyme><IL-1BC><IL-1b Converting Enzyme><IL1B-Convertase><IL1BC><IL1BCE><Image><Impaired cognition><Impaired health><Inflammation Mediators><Inflammatory><Interleukin 1-B Converting Enzyme><Interleukin 1-Beta Convertase><Interleukin-1 Beta Converting Enzyme><Interleukin-1 Converting Enzyme><Intracranial Vascular Diseases><Intracranial Vascular Disorders><KO mice><Knock-out Mice><Knockout Mice><Laboratories><Leakage><Marrow monocyte><Memory Deficit><Memory impairment><Mental Health><Mental Hygiene><Mice><Mice Mammals><Murine><Mus><Neuronal Dysfunction><Null Mouse><Pathologic><Patients><Pericapillary Cell><Pericytes><Perivascular Cell><Persons><Play><Production><Programmed Cell Death><Psychological Health><Reporting><Research><Role><Rouget Cells><SIC-1><Sepsis><Single-Nucleus Sequencing><Spillage><Survivors><Vascular Cognitive Impairment><Vascular Diseases><Vascular Disorder><antisense oligo><blood flow in brain><blood infection><blood vessel disorder><bloodbrain barrier><bloodstream infection><brain blood circulation><brain blood flow><brain pericytes><brain perivascular cell><brain tissue><brain vascular disease><brain vascular dysfunction><brain vascular pericyte><cerebral blood flow><cerebral circulation><cerebral pericyte><cerebral vascular disease><cerebral vascular dysfunction><cerebrocirculation><cerebrovascular blood flow><cerebrovascular dysfunction><cerebrovascular pericyte><cognitive dysfunction><cognitive loss><compare to control><comparison control><developmental><hippocampal><imaging><improved><inflammatory mediator><intracranial vascular dysfunction><memory dysfunction><model of animal><monocyte><necropsy><neural dysfunction><neural inflammation><neuro-vascular unit><neuroinflammation><neuroinflammatory><neurovascular unit><novel><postmortem><programs><recruit><response><sNuc-Seq><sepsis patients><septic patients><single nucleus RNA-sequencing><single nucleus seq><single-nucleus RNA-seq><snRNA sequencing><snRNA-seq><social role><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><treatment strategy><vascular><vascular and cognitive impairment><vascular cognition impairment><vascular cognitive decline><vascular cognitive disease><vascular cognitive dysfunction><vascular contributions to cognitive impairment><vascular dysfunction><vascular related cognitive decline><vascular related cognitive impairment><vasculopathy>