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Principal Investigator: Betty Diamond
Organization: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
Fiscal Year: 2021
Award: $196,504
Funding agency: National Institute of Allergy and Infectious Diseases
Abstract
There are mechanisms in the brain that regulate interactions between neurons and microglial
cells and promote homeostasis. These are perturbed in several diseases including
neuropsychiatric lupus, NPSLE, studied in this PPG, and following sepsis. Many conditions of
neuroinflammation are characterized by microglial activation, and, as a consequence of this
activation, by neuronal dendritic pruning and an impaired blood brain barrier. Interestingly, a
pathway regulating homeostasis in the brain and dysregulated by neuroinflammation is the
renin-angiotensin system. Angiotensin II is generated by angiotensin converting enzyme, ACE,
and binds to a receptor AT-1 to enhance inflammation. ACE inhibitors or angiotensin receptor
blockers, ARBs, can improve neuroinflammation by either decreasing production or neutralizing
angiotensin II. In this pathway, ACE2, a membrane-bound protease, also functions to destroy
angiotensin and to generate a small angiotensin peptide, ang1-7, that is anti-inflammatory.
ACE2 is the cellular receptor for Covid-19, and binds the viral spike protein, S, more specifically,
the receptor binding domain, RBD. This study will examine the binding of S and RBD to normal
mouse brain and to mouse brain mimicking NPSLE or sepsis survival. We will further study
whether engagement by S or RBD alters the functional state of neurons, microglia and brain
endothelial cells. Finally, we ask whether the use of ACE inhibitors or ARBs alters S or RBD
binding, and whether S or RBD impair the efficacy of these medications in halting or reversing
the neurodegenerative process in NPSLE and in sepsis survivors. This study cannot be
performed in humans, but it has important translational implications.
Terms: <(TNF)-α><ACE Inhibitors><AD dementia><AGTR2><AGTR2 gene><AT2><Address><Affect><Alzheimer><Alzheimer Type Dementia><Alzheimer disease><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's disease dementia><Alzheimers Dementia><Alzheimers disease><AngII><Angiotensin Converting Enzyme><Angiotensin I><Angiotensin I-Converting Enzyme><Angiotensin I-Converting Enzyme Inhibitors><Angiotensin II><Angiotensin Receptor><Angiotensin-Converting Enzyme Antagonists><Angiotensin-Converting Enzyme Inhibitors><Angiotensins><Anti-Hypertensive Agents><Anti-Hypertensive Drugs><Anti-Hypertensives><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antibodies><Antihypertensive Agents><Antihypertensive Drugs><Antihypertensives><Antiinflammatories><Antiinflammatory Agents><Autoregulation><Behavior><Binding><Blood - brain barrier anatomy><Blood-Brain Barrier><Body Tissues><Brain><Brain Nervous System><Brain Pathology><CD143 Antigens><CNS Nervous System><CNS lupus><COVID-19><COVID19><CV-19><CV19><Cachectin><Carboxycathepsin><Cardiac><Cell Body><Cells><Central Nervous System><Central Nervous System Lupus><Central Nervous System Systemic Lupus Erythematosis><Chronic><Cleaved cell><Cognition><Coronaviridae><Coronavirus><Data><Dendrites><Dipeptidyl Peptidase A><Disease><Disorder><Drug usage><Drugs><Effectiveness><Encephalon><Enzyme Gene><Enzymes><Epithelial Cells><Esteroproteases><Exhibits><G Protein-Complex Receptor><G Protein-Coupled Receptor Genes><G(s), alpha Subunit><G(s), α Subunit><G(s)alpha><G(s)α><G-Protein-Coupled Receptors><GPCR><GTP-Binding Protein alpha Subunits, Gs><GTP-Binding Protein α Subunits, Gs><Gene Transcription><Genetic Transcription><Goals><Gs alpha Family G-Protein><Gsα><Gαs><Hemato-Encephalic Barrier><Homeostasis><Hortega cell><Human><Hypotensive Agent><Hypotensive Drugs><Hypotensives><IFN><Immune Cell Activation><Impairment><Individual><Inflammation><Inflammatory Response><Interferons><Kininase A><Kininase II><Kininase II Antagonists><Kininase II Inhibitors><Macrophage-Derived TNF><Mediating><Medication><Membrane><Mice><Mice Mammals><Microglia><Modeling><Modern Man><Molecular Interaction><Monocyte-Derived TNF><Murine><Mus><Nerve Cells><Nerve Degeneration><Nerve Unit><Neural Cell><Neuraxis><Neurocyte><Neuron Degeneration><Neurons><Neuropsychiatric Lupus><Neuropsychiatric SLE><Neuropsychiatric Systemic Lupus Erythematosus><PET><PET Scan><PET imaging><PETSCAN><PETT><Pathologic><Pathology><Pathway interactions><Penetration><Peptidases><Peptide Hydrolases><Peptides><Peptidyl-Dipeptidase A><Peripheral Nervous System><Pharmaceutic Preparations><Pharmaceutical Preparations><Physiological Homeostasis><Positron Emission Tomography Medical Imaging><Positron Emission Tomography Scan><Positron-Emission Tomography><Primary Senile Degenerative Dementia><Process><Production><Protease Gene><Proteases><Proteinases><Proteins><Proteolytic Enzymes><RNA Expression><Rad.-PET><Receptor Protein><Regulatory Ns Protein><Renal Tissue><Renin-Angiotensin System><Role><Sepsis><Stimulatory Gs G-Protein><Survivors><System><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Therapeutic Effect><Tissues><Transcription><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Viral><Virus><alpha Subunit Stimulatory GTP-Binding Protein><alpha-Gs><antiinflammatory><arm><base><blood infection><bloodbrain barrier><bloodstream infection><brain cell><brain endothelial cell><brain health><brain microvascular endothelial cell><brain vascular endothelial cell><cerebral endothelial cell><cerebral microvascular endothelial cell><cerebral vascular endothelial cell><cleaved><corona virus><corona virus disease 2019><coronavirus disease 2019><cytokine><dementia of the Alzheimer type><drug use><drug/agent><enzyme pathway><gitter cell><human disease><human subject><immune activation><improved><in vivo><interest><membrane structure><mesoglia><microglial cell><microgliocyte><mouse model><murine model><neural degeneration><neurodegeneration><neurodegenerative><neuroinflammation><neuroinflammatory><neurological degeneration><neuronal><neuronal degeneration><pathway><perivascular glial cell><positron emission tomographic (PET) imaging><positron emission tomographic imaging><positron emitting tomography><prevent><preventing><primary degenerative dementia><programs><receptor><receptor binding><receptor bound><senile dementia of the Alzheimer type><social role><uptake><α-Gs>