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Principal Investigator: JUAN M SAAVEDRA
Organization: GEORGETOWN UNIVERSITY
Fiscal Year: 2022
Award: $630,502
Funding agency: National Institute of Neurological Disorders and Stroke
SARS-CoV-2, the virus underlying the current COVID-19 pandemic, not only affects peripheral tissues, it also
targets the brain causing microvascular lesions, microhemorrhages and neurological manifestations. The
internalization of SARS-CoV-2 is initiated by the binding of the virus spike protein to angiotensin converting
enzyme 2 (ACE2) on the membrane of host cells including endothelial cells throughout cerebral capillaries.
ACE2 is internalized along with the virus thereby leading to a state of ACE2 deficiency. ACE2 is a critical member
of the renin-angiotensin system (RAS). This enzyme catabolizes the octapeptide hormone angiotensin-[1-8]
thereby protecting cells and tissues from the vasoconstrictor, pro-inflammatory and pro-thrombotic effects of
overactive angiotensin type 1 receptors (AT1Rs). Blocking AT1Rs with an AT1R antagonist protects mice from
behavioral impairments due to ACE2 deficiency. Lipopolysaccharide (LPS) causes microglia activation and
neuronal cell loss and is widely used as an experimental model of neuroinflammation. The brain pathophysiology
induced by LPS shares many similarities with SARS-CoV-2 infection. We hypothesize that under conditions of
reduced ACE2 (i.e., ACE2 knockout mice or SARS-CoV-2-infected hamsters), AT1R activity is upregulated in
the microvasculature. In the presence of an inflammatory insult (i.e., LPS or SARS-CoV-2), AT1Rs promote
endothelial dysfunction in the microvasculature through pro-inflammatory and pro-thrombotic signaling pathways
leading to blood brain barrier injury. Deficits in cognition and increased anxiety ensue. We will test this overall
hypothesis through the following specific aims: Determine the mechanisms of the pro-injury (Aim 1) and
protective (Aim 2) arms of the RAS that regulate the pathophysiology of the brain in animal models of
neuroinflammation and COVID-19. (Aim 3) Determine the mechanisms underlying the effects of biological sex
and age in the brain pathophysiology induced by LPS and SARS-CoV-2. Studying RAS mechanisms in the brain
will provide insight into on-going and future clinical trials of therapeutics for treating brain injury associated with
COVID-19 and other diseases of neuroinflammation. In addition, focusing on mechanisms underlying the effects
of biological sex and age on microvasculature pathophysiology in models of neuroinflammation and COVID-19
will shed light into why male sex and age are major risk factors for COVID-19 severity.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><ACE2><Acquired brain injury><Affect><Age><Ageusia><Aging><Ammon Horn><Angiotensin AT1 Receptor><Angiotensin II Type 1 Receptor><Angiotensin II Type 1 Receptor Antagonists><Angiotensin II Type 1 Receptor Blockers><Angiotensins><Animal Model><Animal Models and Related Studies><Anosmia><Anxiety><Arm Injuries><Attenuated><Autopsy><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF2><Behavior><Beta Proprotein Interleukin 1><Binding><Blood - brain barrier anatomy><Blood Clotting><Blood Coagulation Factor><Blood Coagulation Factor II><Blood Vessels><Blood coagulation><Blood-Brain Barrier><Body Tissues><Brain><Brain Injuries><Brain Nervous System><Brain Pathology><Brain Vascular Disorders><CNS Nervous System><COVID crisis><COVID disease severity><COVID epidemic><COVID infected patient><COVID pandemic><COVID patient><COVID positive patient><COVID severity><COVID-19><COVID-19 affected><COVID-19 consequence><COVID-19 crisis><COVID-19 disease severity><COVID-19 effect><COVID-19 epidemic><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 impact><COVID-19 impacted><COVID-19 infected patient><COVID-19 infection><COVID-19 pandemic><COVID-19 patient><COVID-19 positive patient><COVID-19 public health crisis><COVID-19 related risk><COVID-19 risk><COVID-19 risk factor><COVID-19 severity><COVID-19 virus><COVID19><COVID19 crisis><COVID19 disease severity><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 infection><COVID19 pandemic><COVID19 patient><COVID19 positive patient><COVID19 public health crisis><COVID19 severity><COVID19 virus><CV-19><CV19><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Central Nervous System><Cephalalgia><Cephalgia><Cephalodynia><Cerebral Brain Hemorrhage><Cerebral Hemorrhage><Cerebral Parenchymal Hemorrhage><Cerebral hemisphere hemorrhage><Cerebrovascular Disease><Cerebrovascular Disorders><Cerebrum><Cerebrum Hemorrhage><Clinical Trials><Clotting><CoV-2><CoV2><Coagulation><Coagulation Factor II><Coagulation Factors><Coagulation Process><Cognition><Cognitive><Complement Activation><Confusion><Confusional State><Cornu Ammonis><Cranial Pain><Cricetinae><Differentiation Reversal Factor><Disease><Disorder><Dysfunction><Encephalon><Endocrine Gland Secretion><Endothelial Cells><Endothelium><Enzyme Gene><Enzymes><Exhibits><Experimental Models><Factor II><Fibrin><Functional disorder><Future><Gram-Negative Bacteria><HPGF><Hamsters><Hamsters Mammals><Head Pain><Headache><Hemato-Encephalic Barrier><Hepatocyte-Stimulating Factor><Hippocampus><Hippocampus (Brain)><Homolog of Drosophila TOLL><Hormonal><Hormones><Hortega cell><Hybridoma Growth Factor><IFN-beta 2><IFNB2><IL-1 beta><IL-1 β><IL-1-b><IL-1β><IL-6><IL1-Beta><IL1-β><IL1B Protein><IL1F2><IL1β><IL6 Protein><Immunoglobulin Enhancer-Binding Protein><Impairment><Infiltration><Inflammation><Inflammatory><Injury><Interleukin 1beta><Interleukin-1 beta><Interleukin-1β><Interleukin-6><Intracellular Communication and Signaling><Intracerebral Hemorrhage><Intracranial Vascular Diseases><Intracranial Vascular Disorders><Ischemic Stroke><KO mice><Knock-out Mice><Knockout Mice><Lesion><Light><Lipopolysaccharides><Lung><Lung Respiratory System><MGI-2><Membrane><Mental Confusion><Mice><Mice Mammals><Microglia><Modeling><Molecular Interaction><Murine><Mus><Myeloid Differentiation-Inducing Protein><NF-kB><NF-kappa B><NF-kappaB><NFKB><Nerve Cells><Nerve Unit><Neural Cell><Neuraxis><Neurocyte><Neurologic Manifestations><Neurologic Signs and Symptoms><Neurologic Symptoms><Neurological Manifestations><Neurological Signs and Symptoms><Neurons><Nuclear Factor kappa B><Nuclear Transcription Factor NF-kB><Null Mouse><Pathology><Pathway interactions><Peripheral><Pharmaceutical Agent><Pharmaceuticals><Pharmacologic Substance><Pharmacological Substance><Phlebothrombosis><Photoradiation><Physiopathology><Plasmacytoma Growth Factor><Platelet Activation><Play><Preinterleukin 1 Beta><Production><Proteins><Prothrombin><Receptor, Angiotensin, Type 1><Renin-Angiotensin System><Reporting><Research><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 disease severity><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 pandemic><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 severity><SARS-CoV2><SARS-CoV2 epidemic><SARS-CoV2 infection><SARS-CoV2 pandemic><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><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 CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><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 epidemic><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome related corona virus 2><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Symptoms><TIL4><TLR2><TLR2 gene><TLR2 receptor><TLR4><TLR4 gene><Testing><Therapeutic Clinical Trial><Therapeutic Hormone><Thrombase><Thrombin><Thrombosis><Tissues><Toll Homologue><Toll-Like Receptor 2><Toll/Interleukin 1 Receptor-Like 4><Toll/Interleukin 1 Receptor-Like 4 Gene><Toll/Interleukin 1 Receptor-Like Protein 4><Transcription Factor NF-kB><Type 1 Angiotensin Receptor Antagonists><Type 1 Angiotensin Receptor Blockers><Vasoactive Agonists><Vasoconstrictor Agents><Vasoconstrictor Drugs><Vasoconstrictors><Vasopressor Agents><Venous Thrombosis><Viral><Virus><Wuhan coronavirus><ages><angiotensin converting enzyme 2><angiotensin converting enzyme II><anosphrasia><arm><behavioral impairment><biological adaptation to stress><biological sex><biological signal transduction><bloodbrain barrier><brain capillary><brain damage><brain endothelial cell><brain microvascular endothelial cell><brain microvasculature><brain microvessels><brain parenchyma><brain vascular disease><brain vascular dysfunction><brain vascular endothelial cell><brain-injured><cerebral><cerebral capillary><cerebral endothelial cell><cerebral microvascular endothelial cell><cerebral microvasculature><cerebral microvessels><cerebral vascular><cerebral vascular disease><cerebral vascular dysfunction><cerebral vascular endothelial cell><cerebro-vascular><cerebrovascular><cerebrovascular dysfunction><clotting factor><complement pathway regulation><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronavirus disease 2019><coronavirus disease 2019 consequence><coronavirus disease 2019 crisis><coronavirus disease 2019 disease severity><coronavirus disease 2019 effect><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 impact><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 pandemic><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 public health crisis><coronavirus disease 2019 risk><coronavirus disease 2019 risk factor><coronavirus disease 2019 severity><coronavirus disease 2019 virus><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease infected patient><coronavirus disease pandemic><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease severity><coronavirus disease-19><coronavirus disease-19 global pandemic><coronavirus disease-19 impact><coronavirus disease-19 pandemic><coronavirus disease-19 patient><coronavirus disease-19 virus><coronavirus infectious disease-19><coronavirus patient><cytokine><endothelial dysfunction><experiment><experimental research><experimental study><fibrinogenase><gitter cell><hCoV19><head ache><hippocampal><immune cell-mediated thrombosis><immune-mediated thrombosis><immunothrombosis><immunothrombotic><impaired behavior><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><injuries><insight><interferon beta 2><intracranial vascular dysfunction><kappa B Enhancer Binding Protein><loss of smell><male><member><membrane structure><mesoglia><microglial cell><microgliocyte><model of animal><model organism><nCoV2><necropsy><nerve cell death><nerve cell loss><neural manifestation><neuroinflammation><neuroinflammatory><neuron cell death><neuron cell loss><neuron death><neuron loss><neuronal><neuronal cell death><neuronal cell loss><neuronal death><neuronal loss><nuclear factor kappa beta><olfactory loss><overexpress><overexpression><pathophysiology><pathway><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><perivascular glial cell><postmortem><pulmonary><reaction; crisis><risk associated with COVID-19><risk factor associated with COVID-19><risk factor related to COVID-19><risk related to COVID-19><severe acute respiratory syndrome coronavirus 2 disease severity><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><severe acute respiratory syndrome coronavirus 2 severity><sex><social role><stress response><stress; reaction><taste loss><thrombotic><thrombotic disease><thrombotic disorder><toll-like receptor 4><vascular><vasopressor>