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Principal Investigator: Olatundun Dupe Awosanya
Organization: INDIANA UNIVERSITY INDIANAPOLIS
Fiscal Year: 2024
Award: $41,715
Funding agency: National Institute on Aging
PROJECT SUMMARY/ABSTRACT
The Coronavirus Disease 2019 (COVID-19) pandemic as of June 14, 2021, has totaled 176.02 million
cases, 3.80 million deaths, and 2.37 billion vaccine doses have been administered globally. However, many
have suffered prior to the vaccine and have survived or will still suffer without the vaccine. Therefore,
determining the possible long-term health ramifications post-infection, how they vary based on age at the time
of infection, and whether disease severity differentially impacts long-term health is imperative. Information on
how COVID-19 affects bone metabolism and homeostasis is limited. This is of crucial concern because the
aging population generally has higher bone loss and are at the highest risk of developing severe COVID-19
infection. The objective of the current application is to determine whether long-term deficits in bone mass
are experienced following SARS-CoV-2 infection. The long-term goal is to develop potential treatment
strategies to combat COVID-19 related bone loss. Preliminary studies showed that in a K18-hACE2 mouse
model of COVID-19, surviving mice infected with 1x103 or 1x104 PFU exhibited up to a 24% reduction in
trabecular bone volume fraction just 2 weeks post infection (p<0.001). Infected mice had a 63% increase in
osteoclast numbers (p<0.0002) and a 30% increase in surface occupied by osteoclasts (p<0.02) compared to
non-infected controls. Additionally, mice infected with any dose of SARS-CoV-2 had a 40% increase in
megakaryocytes (MKs) within their femoral bone marrow compared to that observed in mock-infected controls
(p<0.008). Further, previously conducted studies showed that MKs regulate bone mass and osteoclast (OC)
formation (aged MKs increase OCs and have increased RANKL expression). Moreover, patients with severe
forms of COVID-19 have upregulated expression of numerous cytokines and growth factors which is known as
an inflammatory cytokine storm. Many of these cytokines, including IL-6 and TNF-α, are known to regulate
OCs and/or MKs and may be responsible for the bone loss observed in the preliminary studies. Based on
these observations it is hypothesized that i) SARS-CoV-2 infection results in long-term health complications in
the musculoskeletal system, and ii) SARS-CoV-2 infection and the associated cytokine storm increases MK-
stimulated OC formation. To test this hypothesis, two specific aims will be pursued: 1- determine whether
following SARS-CoV-2 infection the bone loss observed remains over time and whether age at the time of
infection impacts the severity of bone loss induced by SARS-CoV-2 infection, and: 2- investigate the
mechanisms by which OC formation and bone resorption are increased as a consequence of SARS-CoV-2
infection and age, including the extent to which MKs from infected mice induce OC formation and bone
resorption. The successful completion of these studies will deepen the understanding of the health implications
post-infection with SARS-COV-2 and will demonstrate how disease severity, age, and MKs influence skeletal
homeostasis as well as OC formation and resorption.
Terms: <(TNF)-α><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><Age><Age Months><Area><Autopsy><Autoregulation><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><Beta Proprotein Interleukin 1><Blood Platelet Count><Blood Platelet Number><Blood Platelets><Blood Serum><Blood megakaryocyte><Body System><Body Weight><Bone Inflammation><Bone Marrow><Bone Marrow Reticuloendothelial System><Bone Resorption><Brain><Brain Nervous System><COVID complications><COVID crisis><COVID disease severity><COVID epidemic><COVID infected patient><COVID pandemic><COVID patient><COVID positive patient><COVID related complications><COVID severity><COVID-19><COVID-19 affected><COVID-19 complications><COVID-19 consequence><COVID-19 crisis><COVID-19 disease severity><COVID-19 effect><COVID-19 epidemic><COVID-19 era><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 negative><COVID-19 pandemic><COVID-19 patient><COVID-19 period><COVID-19 positive patient><COVID-19 public health crisis><COVID-19 related complications><COVID-19 severity><COVID-19 virus><COVID-19 virus infection><COVID-19 years><COVID19 disease severity><COVID19 infection><COVID19 negative><COVID19 patient><COVID19 positive patient><COVID19 severity><COVID19 virus><CRG-2><CTLA-8><CTLA-8 Gene><CTLA8><CTLA8 Gene><CV-19><CXCL10><CXCL10 gene><Cachectin><Cancellous bone><Cardiac><Cell Body><Cells><Cessation of life><Clinical><CoV-2><CoV2><Conditioned Culture Media><Conditioned Medium><Contracting Opportunities><Contracts><Coronavirus Infectious Disease 2019><Cytotoxic T-Lymphocyte-Associated Antigen 8><Cytotoxic T-Lymphocyte-Associated Antigen 8 Gene><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8 Gene><Data><Death><Disease><Disorder><Dose><Encephalon><Epidemic><Euthanasia><Exhibits><Femur><General Population><General Public><Goals><Growth Agents><Growth Factor><Growth Substances><HPGF><Health><Heart><Hepatocyte-Stimulating Factor><Histologic><Histologically><Homeostasis><Human Figure><Human body><Hybridoma Growth Factor><Hypercoagulability><IFI10><IFN-beta 2><IFNB2><IL-1 beta><IL-1 β><IL-1-b><IL-17><IL-17 Gene><IL-17A><IL-17A Gene><IL-1β><IL-6><IL1-Beta><IL1-β><IL17><IL17 Protein><IL17 gene><IL17A><IL17A Gene><IL1B Protein><IL1F2><IL1β><IL6 Protein><INP10><IP-10><Infection><Inflammatory><Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8)><Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8) Gene><Interleukin 17 Precursor><Interleukin 17 Precursor Gene><Interleukin 1beta><Interleukin-1 beta><Interleukin-17><Interleukin-1β><Interleukin-6><K-18><K-18 conjugate><K18><K18 combination><Laboratories><Lead><Light><Lung><Lung Respiratory System><MGDF><MGDF Factor><MGI-2><MOB-1><Macrophage-Derived TNF><Marrow platelet><Megakaryocyte Colony Stimulating Factor><Megakaryocyte Growth and Development Factor><Megakaryocytes><Megalokaryocyte><Mercy Killing><Mice><Mice Mammals><Monitor><Monocyte-Derived TNF><Murine><Mus><Musculoskeletal><Musculoskeletal System><Myeloid Differentiation-Inducing Protein><Myeloproliferative Leukemia Virus Oncogene Ligand><OPGL><OSF gene><OSF protein><OSTF1><OSTF1 gene><Older Population><Organ><Organ System><Osteitis><Osteoclast-Stimulating Factor 1><Osteoclastic Bone Loss><Osteoclasts><Osteoporosis><Patients><Pb element><Photoradiation><Physiological Homeostasis><Plasmacytoma Growth Factor><Platelet Count><Platelet Count measurement><Platelet Number><Platelets><Population><Posture><Predisposition><Preinterleukin 1 Beta><Proteins Growth Factors><RANKL><Reporting><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 negative><SARS-CoV-2 pandemic><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 severity><SARS-CoV2><SARS-CoV2 infection><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><SCYB10><SH3P2><Serum><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 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><Severities><Severity of illness><Skeleton><Surface><Susceptibility><System><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFSF11><TNFSF11 gene><TNFα><Testing><Thrombocytes><Thrombocytopoiesis-Stimulating Factor><Thrombocytopoietin><Thrombophilia><Thrombopoietin><Thrombus><Time><Titrations><Transgenic Mice><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Vaccines><Viral Burden><Viral Load><Viral Load result><Wuhan coronavirus><after COVID-19 infection><after SARS-CoV-2 infection><after SARS-CoV2 infection><after infection by SARS-CoV-2><after severe acute respiratory distress syndrome CoV-2 infection><aged><aged group><aged groups><aged individual><aged individuals><aged mice><aged mouse><aged people><aged person><aged persons><aged population><aged populations><ages><aging population><bone><bone loss><bone mass><bone metabolism><bone turnover><c-mpl Ligand><cohort><combat><complications due to COVID-19><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 negative><coronavirus disease 2019 pandemic><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 public health crisis><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><cytokine release syndrome><cytokine storm><disease model><disease severity><disorder model><elderly mice><experience><following COVID-19 infection><following SARS-CoV-2 infection><following SARS-CoV2 infection><following infection by SARS-CoV-2><following severe acute respiratory distress syndrome CoV-2 infection><gIP-10><hCoV19><hRANKL2><heavy metal Pb><heavy metal lead><high risk><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><inflamed bone><interferon beta 2><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><locomotor system><mortality><mouse model><mpl Ligand><murine model><nCoV2><necropsy><old mice><older groups><older individuals><older person><osteoclast progenitor><osteoclast stimulating factor><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><population aging><post SARS-CoV-2 infection><postmortem><previous COVID-19 infection><previous SARS-CoV-2 infection><previous SARS-CoV2 infection><previous severe acute respiratory distress syndrome CoV-2 infection><prior COVID-19 infection><prior SARS-CoV-2 infection><prior SARS-CoV2 infection><prior severe acute respiratory distress syndrome CoV-2 infection><pulmonary><sOdf><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 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 negative><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><severe acute respiratory syndrome coronavirus 2 severity><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><skeletal><skeletons><substantia spongiosa><substantia trabecularis><trabecular bone><treatment strategy>