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Principal Investigator: HUAFENG WEI
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2021
Award: $332,767
Funding agency: National Institute on Aging
Abstract
Coronavirus disease 2019 (COVID-19), a pandemic affecting millions of patients around
the world, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with no
effective drug treatments. Both infection and transfection of virus in host cells require
abnormally elevated Ca2+ concentrations in cytosol and endosome via overactivation of
ryanodine receptors (RyRs) Ca2+ channel located on the membrane of the endoplasmic
reticulum (ER). Dantrolene, an antagonist of RyRs, has been demonstrated to inhibit SARS-
CoV-2-mediated host cell toxicity and damage. In the presence of RyRs overactivation and
excessive and abnormal elevation of cytosolic and endosome Ca2+ concentrations, the spike
proteins (S1, S2) of the virus play important roles in binding, fusion, and virus replication in the
host cell, eventually leading to cell damage or death. Our long-term goal is to examine the
efficacy and mechanisms of dantrolene to treat AD. The overall objective of this study is to
investigate the effects and underlying mechanisms of dantrolene to protect against host cell
damage or death induced by SARS-CoV-2 spike proteins-mediated overactivation of RyRs and
associated Ca2+ dysregulation. Our central hypothesis supported by preliminary data is that
dantrolene inhibits SARS-CoV-2 spike proteins-mediated cell damage by inhibiting the
overactivation of RyRs and by restoring intracellular Ca2+ homeostasis in AD cells. We
will test this hypothesis with the following specific aims. Specific Aim 1 (SA1). To determine
the effects of dantrolene on SARS-CoV-2 spike (S) proteins-mediated Ca2+ dysregulation
and cell damage by apoptosis in AD cells using induced pluripotent stem cells (iPSC), from
skin fibroblasts of patients with either sporadic (SAD) or familial (FAD), and human
neuroblastoma cells (SH-SY5Y), with knocked-in AD presenilin 1 mutation (M146L). Specific
Aim 2 (SA2). To determine the effects and mechanisms of dantrolene on SARS-CoV-2
spike (S) proteins-mediated pathological pathways leading to host cell damage. We will
examine the effects of S proteins on mitochondria oxygen consumption, ATP production,
reactive oxygen species (ROS) production, ER stress, and cytokine release. We will correlate
the results between SA1 and SA2. We expect that dantrolene will inhibit S proteins-mediated
overactivation of RyRs and associated disruption of intracellular Ca2+ homeostasis and cell
death by apoptosis.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><ACE2><AD dementia><Active Oxygen><Address><Affect><Alzheimer><Alzheimer Type Dementia><Alzheimer disease><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's disease dementia><Alzheimer's disease patient><Alzheimer's patient><Alzheimers Dementia><Alzheimers disease><Apoptosis><Apoptosis Pathway><Autoregulation><Binding><CATL><COVID infected patient><COVID patient><COVID positive patient><COVID-19><COVID-19 S protein><COVID-19 infected patient><COVID-19 infection><COVID-19 patient><COVID-19 positive patient><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 therapy><COVID-19 treatment><COVID-19 virus><COVID19><COVID19 S protein><COVID19 infection><COVID19 patient><COVID19 positive patient><COVID19 spike glycoprotein><COVID19 spike protein><COVID19 therapy><COVID19 treatment><COVID19 virus><CTSL Protein><CV-19><CV19><Ca Release Channel-Ryanodine Receptor><Calcineurin><Calcium-Ryanodine Receptor Complex><Cathepsin L><Cathepsins><Cell Body><Cell Death><Cell Nucleus><Cell membrane><Cells><Cellular injury><Cessation of life><Clinical><Clinical Research><Clinical Study><CoV-2><CoV2><Cytoplasmic Membrane><Cytosol><Dantrolene><Data><Death><Dose><Drug Therapy><Drugs><Dysfunction><ER stress><Endocytosis><Endoplasmic Reticulum><Endosomes><Epithelial><Ergastoplasm><Exposure to><Fibroblasts><Functional disorder><Future><Gene Transcription><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Goals><Grant><Homeostasis><Human><Impairment><Infection><Kidney><Kidney Urinary System><Knock-in><Lysosomes><Major Excreted Protein><Mediating><Medication><Membrane><Mitochondria><Modeling><Modern Man><Molecular Interaction><Mutation><NF-AT><NF-AT proteins><NFAT proteins><NFAT-1><NFATC proteins><NPC><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Nuclear Pore Complex><Nucleus><O element><O2 element><Oxygen><Oxygen Consumption><Oxygen Radicals><PP2B><PSEN1><Parents><Pathologic><Pathway interactions><Patients><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacotherapy><Physiological Homeostasis><Physiopathology><Plasma Membrane><Play><Primary Senile Degenerative Dementia><Pro-Oxidants><Process><Production><Progenitor Cells><Programmed Cell Death><Protein Phosphatase-2B><Proteins><RNA Expression><RNA replication><Reactive Oxygen Species><Receptor Protein><Receptosomes><Reporting><Risk Factors><Role><Ryanodine Receptor><Ryanodine Receptor Calcium Release Channel><Ryanodine Receptors><S182 protein><SARS corona virus 2><SARS-CoV-2><SARS-CoV-2 S protein><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 inhibitor><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV-2 therapy><SARS-CoV-2 treatment><SARS-CoV2><SARS-CoV2 S protein><SARS-CoV2 infection><SARS-CoV2 spike glycoprotein><SARS-CoV2 spike protein><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><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 S protein><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 inhibitor><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome related corona virus 2><Skin><Stress><Testing><Toxic effect><Toxicities><Transcription><Transfection><Viral Diseases><Virus><Virus Diseases><Virus Replication><Wuhan coronavirus><aged><angiotensin converting enzyme 2><angiotensin converting enzyme II><block SARS-CoV-2><block severe acute respiratory syndrome coronavirus 2><cell damage><cell injury><cellular damage><corona virus disease 2019><coronavirus disease 2019><coronavirus disease 2019 S protein><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 therapy><coronavirus disease 2019 treatment><coronavirus disease 2019 virus><coronavirus disease infected patient><coronavirus disease patient><coronavirus disease positive patient><coronavirus patient><cytokine><cytokine release syndrome><cytokine storm><cytoplasmic nuclear factor of activated T-cells><damage to cells><dementia of the Alzheimer type><drug repurposing><drug treatment><drug/agent><efficacy analysis><efficacy assessment><efficacy evaluation><efficacy examination><endoplasmic reticulum stress><evaluate efficacy><examine efficacy><experiment><experimental research><experimental study><genome mutation><hCoV19><iPS><iPSC><iPSCs><induced pluripotent stem cell><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><inhibit SARS-CoV-2><inhibit severe acute respiratory syndrome coronavirus 2><inhibitor><inhibitor/antagonist><injury to cells><knockin><membrane structure><mitochondrial><nCoV2><necrocytosis><neuroblastoma cell><neurogenesis><neuronal><neuroprotection><nuclear factors of activated T-cells><pandemic><pandemic disease><pathophysiology><pathway><patient infected with 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effect><social role><stem cells><synapse formation><synaptogenesis><transcription factor NF-AT><translational study><treat COVID-19><treat COVID19><treat SARS-CoV-2><treat coronavirus disease 2019><treat severe acute respiratory syndrome coronavirus 2><viral RNA><viral infection><viral multiplication><viral replication><virus RNA><virus infection><virus multiplication><virus-induced disease>