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Principal Investigator: Midori A Yenari
Organization: VETERANS AFFAIRS MED CTR SAN FRANCISCO
Fiscal Year: 2024
Funding agency: Veterans Affairs
This project will explore calcium-release-activated calcium channels (CRAC) as a potential
therapeutic target in a laboratory model of traumatic brain injury (TBI). TBI is a common problem in
the Veteran and civilian populations but definitive treatments are few. Microglia are the brain’s
resident immune cell, and many studies have now shown that when activated, they contribute
negatively to neurological outcome. Thus, strategies to inhibit microglial functions could prove
therapeutic. Recent work has focused on the role of CRAC channels in inflammatory cells such as T
cells, mast cells and neutrophils, and other inflammatory conditions such as autoimmune disease and
acute pancreatitis; however, very little work has been published on CRAC channels as they pertain to
microglia or inflammation in the brain. Past work has focused on calcineurin inhibitors such as
cyclosporine A and FK 506 which act downstream of the CRAC channel, but have many off target
effects and clinical toxicities which limit their use. These CRAC channel inhibitors are already being
studied at the clinical level for other indications, and do not appear to have the same toxicities as the
CNIs. In fact, a similar inhibitor produced by the same company was recently shown to improve
outcome from severe COVID-19 pneumonia following infection with the SARS-CoV-2 virus, and was
well tolerated in this patient population. Prior work in our lab showed that these specific CRAC
channel inhibitors block microglial activation and that at least one of these inhibitors protects the brain
from experimental TBI. This project will study CRAC channel inhibitors in a model of TBI to further
define the conditions where neuroprotection may be observed. The first Aim will determine the more
protective of two such novel CRAC channel inhibitors, and determine the optimal dosing required for
maximum neurological benefit. This aim will also validate the specificity of the inhibitors and the
expected mechanism of action of downstream calcium and inflammatory signaling. The second aim
will then determine whether treatment can be delayed by hours and still show improvement in
neurological outcomes. The third aim will then use the optimal dose and dosing regimen determined
from the first two aims to see if any benefit is long lasting. In vivo experiments will include studies in
female animals as well as comparing these novel, specific inhibitors to currently available, but less
specific inhibitors.
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Stroke><Ciclosporin><Clinical><CoV-2><CoV2><Collaborations><CsA><Cyclosporin A><Cyclosporine><Cyclosporine A><Cytoprotection><Dose><Effects of calcineurin in Keratinocyte Differentiation><Encephalon><Experimental Models><FK 506><FK506><Female><Hortega cell><Hour><Human><Immune><Immune reaction><Immune response><Immune signaling><Immunes><Immunological response><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><In Vitro><Infection><Inflammation><Inflammatory><Inflammatory Response><Injury><Intracellular Communication and Signaling><Laboratories><Length><Lung Inflammation><Marrow Mast Cell><Marrow Neutrophil><Mediating><Mice><Mice Mammals><Microglia><Modeling><Modern Man><Molecular Interaction><Murine><Mus><Nervous System Injuries><Nervous System Trauma><Nervous System damage><Neurologic><Neurologic outcome><Neurological><Neurological Damage><Neurological Injury><Neurological outcome><Neurological trauma><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Outcome><PP2B><Pathway interactions><Plasma><Plasma Serum><Pneumonitis><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Population><Protein Phosphatase-2B><Publishing><Pulmonary Inflammation><Regimen><Regulation><Reticuloendothelial System, Serum, Plasma><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 associated pneumonia><SARS-CoV-2 induced pneumonia><SARS-CoV-2 pneumonia><SARS-CoV-2 related pneumonia><SARS-CoV-2 viral pneumonia><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sandimmun><SangCya><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 coronavirus 2><Severe acute respiratory syndrome related corona virus 2><Signal Transduction><Signal Transduction Systems><Signaling><Site><Source><Specificity><Stroke><T-Cells><T-Lymphocyte><Tacrolimus><Testing><Therapeutic><Tissue Basophils><Toxic effect><Toxicities><Translations><Traumatic Brain Injury><Up-Regulation><Upregulation><VDCC><Veterans><Virus><Voltage-Dependent Calcium Channels><Woman><Women's study><Work><Wuhan coronavirus><acute COVID-19><acute SARS-CoV-2 infection><acute pancreatitis><acute phase of COVID-19><acute phase of SARS-CoV-2 infection><autoimmune condition><autoimmune disorder><autoimmunity disease><biological signal transduction><brain attack><brain damage><brain tissue><brain-injured><cerebral vascular accident><cerebrovascular accident><cohort><coronavirus disease 2019 associated pneumonia><coronavirus disease 2019 induced pneumonia><coronavirus disease 2019 pneumonia><coronavirus disease 2019 related pneumonia><coronavirus disease 2019 virus><coronavirus disease associated pneumonia><coronavirus disease induced pneumonia><coronavirus disease pneumonia><coronavirus disease related pneumonia><coronavirus disease-19 pneumonia><coronavirus disease-19 virus><cytoprotective><effective therapy><effective treatment><experiment><experimental research><experimental study><experiments><female study><gitter cell><glial activation><glial cell activation><hCoV19><host response><immune suppression><immune suppressive activity><immune suppressive function><immune system response><immunoreaction><immunoresponse><immunosuppressive activity><immunosuppressive function><immunosuppressive response><improved><improved outcome><in vivo><inhibitor><injuries><knock-down><knockdown><life-threatening COVID><life-threatening COVID-19><life-threatening SARS-CoV-2><life-threatening coronavirus disease><life-threatening coronavirus disease 2019><life-threatening severe acute respiratory syndrome coronavirus 2><male><mast cell><mastocyte><men><mesoglia><microglial cell><microgliocyte><nCoV2><neoral><neuroprotection><neuroprotective><neurotrauma><neutrophil><novel><pathway><patient population><perivascular glial cell><pneumonia due to COVID><pneumonia due to COVID-19><pneumonia due to SARS-CoV-2><pneumonia due to coronavirus disease><pneumonia due to coronavirus disease 2019><pneumonia due to severe acute respiratory syndrome coronavirus 2><pneumonia in COVID><pneumonia in COVID-19><pneumonia in SARS-CoV-2><pneumonia in coronavirus disease><pneumonia in coronavirus disease 2019><pneumonia in severe acute respiratory syndrome coronavirus 2><prevent><preventing><response><sandimmune><serious COVID><serious COVID-19><serious SARS-CoV-2><serious coronavirus disease><serious coronavirus disease 2019><serious severe acute respiratory syndrome coronavirus 2><severe COVID><severe COVID-19><severe COVID19><severe SARS-CoV-2><severe acute respiratory syndrome coronavirus 2 associated pneumonia><severe acute respiratory syndrome coronavirus 2 induced pneumonia><severe acute respiratory syndrome coronavirus 2 pneumonia><severe acute respiratory syndrome coronavirus 2 related pneumonia><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><side effect><small molecular inhibitor><small molecule inhibitor><social role><stroke model><stroked><strokes><study among females><study among women><study in females><study in women><study on females><study on women><study within women><therapeutic target><thymus derived lymphocyte><translation><traumatic brain damage>