Document text
Principal Investigator: Timothy Tun Hla
Organization: BOSTON CHILDREN'S HOSPITAL
Fiscal Year: 2024
Award: $712,226
Funding agency: National Heart Lung and Blood Institute
SUMMARY
Endothelial cell (EC) dysfunction is a key factor that promotes poor host defense, pro-thrombotic
cardiovascular complications and bleeding during respiratory viral infections. The applicant’s laboratory has
made long-standing contributions in vascular effects of sphingosine 1-phosphate (S1P), a circulating lipid
mediator important for EC resilience. This protective pathway is preferentially activated by HDL-bound S1P, thus
counteracting EC dysfunction and pathophysiology. However, the role of S1P in influenza viral infections in the
context of thrombosis and bleeding complications is poorly understood. This proposal develops a novel paradigm
to enhance vascular resilience while minimizing thrombotic and bleeding complications during virus-induced
pulmonary injury. We have developed designer HDL-like nanoparticles that chaperone S1P, namely, ApoA1-
ApoM (A1M)/S1P, for therapeutic activation of EC S1PR1 and suppression of vascular leak. A1M/S1P either
alone or together with other barrier protective agents such as angiopoietin-1 (ANGPT-1) and prostacyclin (PGI2)
enhanced EC barrier function in endothelial cells. In addition, the ApoA1 moiety of A1M suppressed cytokine-
induced NFkB activation and inflammatory gene expression. We hypothesize that sustained activation of
S1PR1/Gi signaling by HDL-S1P and cooperative interactions between EC protective pathways (ANGPT1/
Tie2 and PGI2/IP receptor) enhances pulmonary vascular recovery from respiratory viral infections
without inducing prothrombotic transformation of the endothelium. Specific aim 1 will evaluate HDL-S1P
activation of protective endothelial S1PR1/Gi signaling. Genetic mouse models of S1PR1 loss of function (EC
knockout), gain of function (EC transgenic) and Gi-biased signaling (S5A phosphorylation-defective mutant),
Apom KO or Apom TG mice will be analyzed to determine alveolar microvascular leak, integrity, thrombosis,
bleeding and resolution of inflammation during influenza virus-induced pneumonitis. Single cell (sc)RNA-seq
data from mice with viral pneumonitis will be deconvoluted to determine molecular mechanisms of paracrine
signal networks between EC and pericytes important in microvascular resilience. The second aim will determine
the mechanisms by which albumin-S1P/S1PR1 signaling in EC promotes thrombosis in the context of viral
infection. We will use Tie2 agonists together with EC-targeted S1PR1 agonists to control bleeding in the setting
of influenza infection. The third aim will develop combinatorial therapeutic approaches containing novel HDL-like
nanoparticles and Tie2 activators to suppress EC injury and thromboinflammation during viral host defense
responses. Designer HDL particles containing S1P that enhances the vascular resilience and HDL particles that
carry stable prostacyclin (PGI2) analogs will be combined with Tie2 activators to suppress thrombosis and
bleeding in lung on chip and mouse models. Together, this proposal aims to achieve a mechanistic
understanding of EC pathophysiology during respiratory viral infections and develop novel therapeutic strategies.
Terms: <ANG1><ANG1 Gene><ANGPT1><ANGPT1 gene><Adventitial Cell><Adverse effects><Agonist><Albumins><Alveolar><Angiopoietin 1 Gene><Angiopoietin-1><Attenuated><Autoregulation><Binding><Bleeding><Blood Clotting><Blood Platelets><Blood Vessels><Blood coagulation><Blood flow><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 years><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular system><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Protection><Cell Signaling><Cell Survival><Cell Viability><Cellular Function><Cellular Physiology><Cellular Process><Cellular injury><Chaperone><Chronic><Cytoprotection><Data><Dedications><Dropout><Dysfunction><Endothelial Cells><Endothelium><Epoprostenol><Fibrosis><Functional disorder><Gene Expression><Genetic><Genetic Models><Grippe><H1N1><H1N1 Virus><HDL><HDL Lipoproteins><Heart Vascular><Heavy Lipoproteins><Hemorrhage><High Density Lipoproteins><High density lipoprotein><Homeostasis><Host Defense><Immunoglobulin Enhancer-Binding Protein><Individual><Inflammation><Inflammatory><Inflammatory Response><Influenza><Influenza A Virus, H1N1 Subtype><Influenza Virus><Injury><Intracellular Communication and Signaling><KIAA0003><Knock-out><Knockout><Laboratories><Lung><Lung Inflammation><Lung Respiratory System><Lung damage><Marrow platelet><Mediating><Mice><Mice Mammals><Modeling><Molecular><Molecular Chaperones><Molecular Interaction><Murine><Mus><NF-kB><NF-kappa B><NF-kappaB><NFKB><Names><Nuclear Factor kappa B><Nuclear Transcription Factor NF-kB><PGI2><Paracrine Communication><Paracrine Signaling><Pathologic><Pericapillary Cell><Pericytes><Perivascular Cell><Phosphorylation><Physiological Homeostasis><Physiopathology><Platelets><Pneumonitis><Process><Prostacyclins><Prostaglandin I2><Prostaglandins I><Protective Agents><Protective Drugs><Protein Phosphorylation><Pulmonary Inflammation><Receptor Cell><Receptor Protein><Recovery><Research><Resolution><Role><Rouget Cells><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Sphingolipids><Subcellular Process><Therapeutic><Thrombocytes><Thrombosis><Transcription Factor NF-kB><Transgenic Organisms><Vascular Diseases><Vascular Disorder><Vascular Endothelial Cell><Viral><Viral Diseases><Viral Respiratory Tract Infection><Virus><Virus Diseases><Work><aged animal><aged animals><alpha-Lipoproteins><analog><animal old age><arrestin B><arteriole><attenuate><attenuates><beta-arrestin><biological signal transduction><blood loss><blood vessel disorder><career><cell damage><cell injury><cell resilience><cell resiliency><cell transformation><cellular damage><cellular resilience><cellular resiliency><circulatory system><combat><combinatorial><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><cytokine><cytokine release syndrome><cytokine storm><cytoprotective><damage to cells><defense response><elderly animal><experiment><experimental research><experimental study><experiments><flu infection><flu virus infection><gain of function><infected with flu><infected with flu virus><infected with influenza><infected with influenza virus><influenza infection><influenza virus infection><influenzavirus><injuries><injury to cells><kappa B Enhancer Binding Protein><lipid mediator><loss of function><lung injury><mortality><mouse model><murine model><mutant><name><named><naming><nano particle><nano-sized particle><nanoparticle><nanosized particle><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><nuclear factor kappa beta><old animals><particle><pathophysiology><physiological defense response><prevent><preventing><prostaglandin X><protection pathway><protective pathway><pulmonary><pulmonary damage><pulmonary injury><pulmonary tissue damage><pulmonary tissue injury><receptor><resilience><resilient><resolutions><respiratory virus><restraint><scRNA-seq><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><small molecule><social role><sphingosine 1-phosphate><targeted agent><thromboinflammation><thromboinflammatory><thrombotic><thrombotic disease><thrombotic disorder><transformed cells><transgenic><vascular><vascular dysfunction><vasculopathy><viral infection><viral respiratory infection><virus infection><virus-induced disease><β-arrestin>