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Principal Investigator: Milka Koupenova
Organization: UNIV OF MASSACHUSETTS MED SCH WORCESTER
Fiscal Year: 2024
Award: $418,750
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY
Influenza infection increases the incidence of acute MI (AMI) within the first 7 days after detection and
the therapeutic benefit of vaccination is comparable to current therapies for secondary prevention of AMI.
Platelets are the blood component central to thrombosis and uncontrolled platelet activation is a major contributor
to unstable coronary syndromes and AMI. Although thrombotic events have been associated with some viral
infections, the molecular mechanisms underlining platelet mediated thrombosis during progression of global viral
infection such as influenza have not been established. The major objective of this proposal is to examine the
role of a previously undescribed molecular mechanism in platelets that leads to sensing of influenza and
ultimately increased thrombosis. The mechanism of reference involves a cytoplasmic receptor known as the
retinoic acid-inducible gene-I (RIG-I) receptor and its downstream signaling cascade. Preliminary results show
that RIG-I and proteins related to RIG-I molecular signaling become specifically upregulated in platelets from
influenza infected patients. Since platelets are anucleated the upregulated expression of RIG-I suggests direct
involvement of their precursors the megakaryocytes (MKs) during infection. For that purpose, we will also study
the contribution of RIG-I in MKs to platelet reprogramming toward more efficient viral response that may lead to
thrombosis. Considering that the RIG-I-signaling axis is present in platelets and specifically upregulated, we
hypothesize that during infection, platelets sense influenza through the RIG-I signaling axis leading to their
activation and MKs reprogram platelets toward an increased antiviral and thrombotic response. Thus, we
propose two specific aims of research: Aim 1. To determine the expression and activity of the RIG-I axis in
platelets with respect to their antiviral and/or thrombotic responses; and Aim 2. To characterize how MKs sense
influenza and how this sensing subsequently reprograms the RIG-I/MAVS pathway, leading to enhanced
expression of antiviral and prothrombotic genes. Building upon novel observations obtained in preliminary
studies, our proposed research plan will determine the role of a previously unknown signaling pathway in
platelets, RIG-I/MAVS, in mediating influenza antiviral and thrombotic responses. The outcome of this proposal
will define the fundamental mechanisms of platelet viral cytosolic signaling, MK response to infection, how this
synergistic response contributes to immunity and thrombosis, and how targeting this pathway could ameliorate
thrombotic and infectious disease pathologies.
Terms: <ATRA><Acute><Acute myocardial infarct><Acute myocardial infarction><Address><Adhesions><Affect><Anti-viral Response><Biology><Blood><Blood Platelets><Blood Reticuloendothelial System><Blood megakaryocyte><Bone Marrow><Bone Marrow Reticuloendothelial System><Cardiovascular Diseases><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cessation of life><Collaborations><Communicable Diseases><Consultations><Coronary><Cytoplasmic Receptors><Death><Detection><Diagnostic><Disease><Disorder><Dysfunction><Event><Functional disorder><Generations><Genes><Goals><Grippe><Human><Immune><Immune response><Immunes><Immunity><Immunological response><Incidence><Incubated><Individual><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Influenza><Intracellular Communication and Signaling><Knock-out><Knockout><Lung><Lung Respiratory System><Marrow platelet><Mediating><Megakaryocytes><Megalokaryocyte><Messenger RNA><Mice><Mice Mammals><Mitochondria><Modeling><Modern Man><Molecular><Murine><Mus><Nature><Non-Polyadenylated RNA><Outcome><Pathogenicity><Pathology><Pathway interactions><Patients><Pattern recognition receptor><Phenotype><Physiopathology><Platelet Activation><Platelets><Principal Investigator><Protein Analysis><Proteins><RNA><RNA Gene Products><RNA Viruses><Receptor Protein><Receptor Signaling><Regulation><Research><Research Proposals><Retinoic Acid><Ribonucleic Acid><Role><Secondary Prevention><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Factor Proto-Oncogene><Signaling Pathway Gene><Signaling Protein><Syndrome><TLR7><TLR7 gene><Therapeutic><Thrombocytes><Thrombosis><Time><Toll-Like Receptor 7><Trans Vitamin A Acid><Tretinoin><Tretinoinum><Up-Regulation><Upregulation><Vaccination><Viral><Viral Diseases><Viremia><Virion><Virus Diseases><Virus Particle><Vitamin A Acid><all-trans-Retinoic Acid><all-trans-Vitamin A acid><antagonism><antagonist><biological signal transduction><burden of disease><burden of illness><cardiovascular disorder><consultation><disease burden><experience><flu><flu infection><flu virus infection><host response><immune system response><immunoresponse><in vivo><infected with flu><infected with flu virus><infected with influenza><infected with influenza virus><influenza infection><influenza virus infection><injury to the vasculature><intervention design><mRNA><mRNA Expression><mitochondrial><mouse model><murine model><novel><pathophysiology><pathway><pharmacologic><programs><pulmonary><receptor><response><social role><therapeutic target><therapy design><thrombotic><thrombotic disease><thrombotic disorder><trans-Retinoic Acid><treatment design><vaccine efficacy><vascular injury><viraemia><viral RNA><viral infection><viral sepsis><virus RNA><virus infection><virus-induced disease><virusemia>