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Principal Investigator: Giulio Maria Pasinetti
Organization: JAMES J PETERS VA MEDICAL CENTER
Fiscal Year: 2024
Funding agency: Veterans Affairs
Project Summary/Abstract
At least 30% of Afghanistan and Iraq veterans are affected by Major Depressive Disorder (MDD) and 20% are
affected by post-traumatic stress disorder (PTSD) and other stress-related mood disorders. Currently existing
pharmacological treatments elicit temporary remission in <50% of patients; thus, there is an urgent need for
novel therapeutic approaches to target MDD and psychological stress-related mood disorders. The prevalence
of MDD is two- to threefold higher in patients with cardiovascular disease and MDD is associated with 80%
increased risk of cardiovascular morbidity and mortality. Clinical studies report higher levels of circulating pro-
inflammatory cytokines in patients with MDD and has been replicated in preclinical animal studies of
depression. Individual differences in the modulation of cytokine release (most notably IL-6) are associated with
susceptibility vs. resilience to chronic social stress in mice. Chronic inflammation and increases in circulatory
pro-inflammatory cytokines associated with stress-induced depression is linked with atherosclerotic plaque
formation, progression, and rupture, likely contributing to the pathogenesis of cardiovascular disease. Indeed,
immune modulatory approaches to neutralize inflammatory cytokines in the periphery produce antidepressant-
like behavioral effects following Chronic Social Defeat Stress (CSDS) in mice as well as in humans with
depression and chronic inflammation. The concept of resilience, the ability to maintain normal psychological
and physical functioning to avoid serious mental illness has topic of significant interest in Veterans during and
post-deployment after exposure to psychological stress.Recently, CSDS-associated depression has been
linked to impairment of the blood brain barrier (BBB), a series of protective layers including endothelial cells
and astrocytes that plays a critical role in maintaining vascular impermeability between the periphery and brain
parenchyma. The proposed validation studies implicate that impairment of the BBB may be causally
associated with stress-induced mood disorders. In particular, we will validate and expand our understanding
how stress influences the region-dependent impairment of the BBB in stress-induced mood disorders, as
previously reported by our collaborators Scott Russo, Anne Schaefer, and Miriam Merad in their publication
“Social stress induces neurovascular pathology promoting depression”. Using a well-characterized CSDS
model of psychological stress in mice that recapitulates many of the symptoms of MDD including social
withdrawal, anhedonia, and anxiety, we will explore through novel technological approaches how chronic
psychological stress impairs the BBB. In particular, we will utilize a novel endothelial-specific Translating
Ribosome Affinity Purification (TRAP) mouse to explore stress-induced transcriptional patterns in multiple
mood-related brain regions to determine transcriptomic patterns to psychological stress. To further explore how
psychological stress impairs the BBB, we will utilize an innovative mass cytometry (CyTOF) to determine the
immune cell profiles in the periphery and brain tissue of susceptible vs. resilient mice and understand how
psychological stress mobilizes the innate immune system and causes infiltration of cytokines into the brain.
In summary, the proposal in this Merit Review Award for Validation Studies is of importance to Veteran Health.
This VA Merit Review Award is to validate recent findings by our collaborators showing that psychological
stress in a model of depression impairs BBB permeability and expand our knowledge into how stress induces
region-specific endothelial gene expression changes, leading to vascular damage and depression-linked
chronic inflammation. The findings of our studies will provide evidence for preclinical studies for novel
therapeutic approaches for treating stress-related MDD for Veterans.
Terms: <Affect><Affective Disorders><Affinity Chromatography><Afghanistan><Anhedonia><Animals><Anxiety><Area><Arterial Fatty Streak><Arterial Fatty Streaks><Astrocytes><Astrocytus><Astroglia><Atheroma><Atheromatous><Atheromatous degeneration><Atheromatous plaque><Automobile Driving><Award><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BAC clone><BACs><BBB penetration><BBB permeabilization><BBB permeable><BCDF><BSF-2><BSF2><Bacterial Artificial Chromosomes><Behavior><Behavioral><Bio-Informatics><Bioinformatics><Blood><Blood - brain barrier anatomy><Blood Reticuloendothelial System><Blood Vessels><Blood monocyte><Blood-Brain Barrier><Brain><Brain Nervous System><Brain region><Cardiovascular Diseases><Cell Body><Cell Communication and Signaling><Cell Signaling><Cell Surface Antigens><Cells><Chronic><Chronic stress><Clinical Research><Clinical Study><Coupled><Cytometry><Data><Development><Disease remission><Encephalon><Endothelial Cells><Endothelium><Epithelium><Exposure to><Expression Signature><Gene Expression><Gene Expression Profile><Gene Transcription><Genes><Genetic Transcription><Goals><HPGF><Health><Hemato-Encephalic Barrier><Hepatocyte-Stimulating Factor><Human><Hybridoma Growth Factor><IFN-beta 2><IFNB2><IL-6><IL6 Protein><Immune><Immune Diseases><Immune Disorders><Immune Dysfunction><Immune System Diseases><Immune System Disorder><Immune System Dysfunction><Immune System and Related Disorders><Immune infiltrates><Immune signaling><Immunes><Immunochemical Immunologic><Immunodeficiency and Immunosuppression Disorders><Immunologic><Immunologic Diseases><Immunologic Surface Markers><Immunological><Immunological Diseases><Immunological Dysfunction><Immunological Surface Markers><Immunological System Dysfunction><Immunologically><Immunologics><Impairment><Individual Differences><Infiltration><Inflammation><Inflammatory><Inflammatory Response><Innate Immune System><Interleukin-6><Intracellular Communication and Signaling><Iraq><Knowledge><Link><MGI-2><Major Depressive Disorder><Marrow monocyte><Measures><Mediating><Mental Depression><Messenger RNA><Mice><Mice Mammals><Modeling><Modern Man><Monitor><Mood Disorders><Moods><Morbidity><Morbidity - disease rate><Murine><Mus><Myeloid Differentiation-Inducing Protein><Nucleus Accumbens><Occluding Junctions><PTSD><Pathogenesis><Pathology><Patients><Pattern><Peripheral><Pharmacological Treatment><Phenotype><Physical Function><Plasmacytoma Growth Factor><Play><Post-Traumatic Neuroses><Post-Traumatic Stress Disorders><Posttraumatic Neuroses><Predisposition><Prevalence><Proteins><Psychologic Models><Psychologic Stress><Psychological Models><Psychological Stress><Publications><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Recruitment Activity><Remission><Reporting><Ribosomes><Role><Rupture><Scientific Publication><Series><Signal Transduction><Signal Transduction Systems><Signaling><Stress><Structure><Surface Antigens><Susceptibility><Symptoms><Testing><Therapeutic><Tight Junctions><Transcription><Translating><Validation><Veterans><Withdrawal><Work><Zonula Occludens><active recruitment><affinity purification><anti-depressant agent><anti-depressant drugs><anti-depressants><anti-depressive agents><anxiety-like behavior><astrocytic glia><atherosclerosis plaque><atherosclerotic lesions><atherosclerotic plaque><behavior phenotype><behavioral phenotyping><biological signal transduction><blood-brain barrier penetration><blood-brain barrier permeabilization><blood-brain barrier permeable><bloodbrain barrier><bloodbrain barrier penetration><bloodbrain barrier permeabilization><bloodbrain barrier permeable><brain parenchyma><brain tissue><cardiovascular disorder><cardiovascular risk><cardiovascular risk factor><chronic mental illness><clinical depression><cytokine><depression><depression model><depressive model><developmental><driving><gene expression pattern><gene expression signature><immune cell infiltrate><innovate><innovation><innovative><interest><interferon beta 2><mRNA><major depression><major depression disorder><monocyte><mortality><neural circuit><neural circuitry><neuro-vascular><neuro-vascular damage><neuro-vascular injury><neurocircuitry><neurovascular><neurovascular damage><neurovascular injury><new technology><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel technologies><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><persistent mental illness><post-trauma stress disorder><posttrauma stress disorder><pre-clinical><pre-clinical study><preclinical><preclinical study><prevent><preventing><psychologic><psychological><recruit><resilience><resilient><response><serious mental disorder><serious mental illness><severe mental disorder><severe mental illness><social><social defeat><social role><social stress><socially stressed><symptomatology><synaptic circuit><synaptic circuitry><transcriptional profile><transcriptional signature><transcriptome sequencing><transcriptomic sequencing><transcriptomics><traumatic neurosis><validation studies><validations><vascular><vulnerable plaque>