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Principal Investigator: Anilkumar Pillai
Organization: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
Fiscal Year: 2022
Award: $445,694
Funding agency: National Institute of Mental Health
Chronic stress is a risk factor for the development of multiple psychiatric disorders for which current treatments are inadequate. Evidence from our laboratory and others suggest that chronic stress can also provoke elevated inflammation and exaggerated inflammatory responses in both humans and animal models. However, the underlying mechanisms are not well understood. Mitochondria become damaged and dysfunctional following chronic stress conditions raising the question of whether neuroinflammation associated with chronic stress-related neuropsychiatric conditions is due to mitochondria-induced inflammation. By removing damaged mitochondria, mitophagy plays a central role in preventing inflammation. When this process is impaired, mtDNA is released and the extracellular cell free mtDNA (cf-mtDNA) promotes Toll-like receptor 9 (TLR9) signaling to activate immune system. Our recent study found that mice exposed to chronic restraint stress (RS) exhibit neuroinflammation and social behavior deficits. Our preliminary data show that depletion of cf-mtDNA with DNase I treatment attenuates RS-induced deficits in social behavior and increases in proinflammatory markers in the prefrontal cortex (PFC). Furthermore, we found that mtDNA-induced deficits in social behavior are TLR9-dependent. Also, RS induced significant increases in TLR9 expression in microglia and neurons. Among the various mitophagy-related molecules, activation of Mitochondrial antiviral-signaling protein (MAVS, a mitochondrial adaptor protein)signaling results in proinflammatory signaling. Our preliminary findings showed that RS-induced increase in cf-mtDNA is attenuated in MAVS KO mice. Also, we found impaired mitophagy in CD4+, but not CDS+ T cells following RS. We hypothesize that increased levels of mtDNA from CD4• T cells contribute to RS-induced neuroinflammation and social behavior deficits via TLR9 activation. Aim 1 will determine whether RS-induced mtDNA release drives neuroinflammation and reduced social behavior. Aim 2 will examine whether mtDNA-mediated activation of TLR9 on neurons promotes social behavior deficits following RS. Aim 3 will examine whether mtDNA release induced by RS is dependent on mitophagy. If successful, our project will create new developments in understanding the mechanism mediating stress-induced neuroinflammation social behavior deficits, and thereby allow the development of pharmacological approaches to inhibit mtDNA release, neutralize extracellular cf-mtDNA, or inhibit TLR9 activation in stress-related mental health disorders.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><Adaptor Protein><Adaptor Protein Gene><Adaptor Signaling Protein><Adaptor Signaling Protein Gene><Affect><Animal Model><Animal Models and Related Studies><Attenuated><Behavioral><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><COVID-19 infection><COVID-19 virus><COVID19 infection><COVID19 virus><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Chemotactic Cytokines><Chronic><Chronic stress><CoV-2><CoV2><Cytosine><DNA><DNA Endonuclease><DNase I><Data><Deoxyribonuclease I><Deoxyribonucleic Acid><Development><Dissection><Dysfunction><Emotional><Exhibits><Exposure to><Functional disorder><Genetic><Goals><Guanine><Homologous Chemotactic Cytokines><Hortega cell><Immune system><Impairment><Inflammation><Inflammatory Response><Intercrines><Intervention><Intervention Strategies><Intracellular Communication and Signaling><KO mice><Knock-out Mice><Knockout Mice><Laboratories><Mediating><Mental Health><Mental Hygiene><Mental disorders><Mental health disorders><Mice><Mice Mammals><Microglia><Mission><Mitochondria><Mitochondrial DNA><Murine><Mus><NIH><NIMH><National Institute of Mental Health><National Institutes of Health><Nerve Cells><Nerve Impulse Transmission><Nerve Transmission><Nerve Unit><Neural Cell><Neurocyte><Neuronal Transmission><Neurons><Null Mouse><Pancreatic DNase><Pharmacology><Phosphates><Physiopathology><Play><Prefrontal Cortex><Process><Psychiatric Disease><Psychiatric Disorder><Psychological Health><Public Health><Risk Factors><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 infection><SARS-CoV2><SARS-CoV2 infection><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SIS cytokines><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome related corona virus 2><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Factor Proto-Oncogene><Signaling Pathway Gene><Signaling Protein><Social Behavior><Stress><Stressful Event><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><TLR9 gene><TLR9 protein><TLR9 receptor><Testing><Therapeutic><Thymonuclease><Treatment Efficacy><United States National Institutes of Health><Work><Wuhan coronavirus><adapter protein><allergic/immunologic body system><allergic/immunologic organ system><antagonist><axon signaling><axon-glial signaling><axonal signaling><biological signal transduction><chemoattractant cytokine><chemokine><coronavirus disease 2019 infection><coronavirus disease 2019 virus><coronavirus disease-19 virus><cytokine><developmental><experiment><experimental research><experimental study><extracellular><fetal><gitter cell><glia signaling><glial signaling><hCoV19><human model><improved><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><inorganic phosphate><insight><intervention efficacy><interventional strategy><mental health related disorder><mental illness><mesoglia><microglial cell><microgliocyte><mitochondrial><model of animal><model of human><model organism><mtDNA><nCoV2><nerve signaling><neural signaling><neuroinflammation><neuroinflammatory><neuronal><neuronal signaling><neuropsychiatric><neuropsychiatric disease><neuropsychiatric disorder><neuropsychiatry><neurotransmission><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><pathophysiology><perivascular glial cell><prevent><preventing><psychiatric illness><psychological disorder><response><restraint stress><social><social defects><social deficits><social disorders><social dysfunction><social role><sociobehavior><sociobehavioral><stressful experience><stressful life event><stressful life experience><therapeutic efficacy><therapy efficacy><thymus derived lymphocyte><toll-like receptor 9>