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Principal Investigator: KATYA RAVID
Organization: BOSTON UNIVERSITY MEDICAL CAMPUS
Fiscal Year: 2024
Award: $412,500
Funding agency: National Heart Lung and Blood Institute
ABSTRACT
Platelet counts are tightly regulated in order to prevent thrombotic or hemorrhagic complications associated
with thrombocytosis or thrombocytopenia, respectively. While strides have been made in our understanding of
proplatelet formation (PPF), there is still limited knowledge regarding the mechanisms through which the bone
marrow (BM) extracellular matrix (ECM) regulates platelet production. Indeed, the BM includes a rich ECM with
potential to generate mechanical constraints. Yet, the impact of BM mechanics on megakaryocyte (MK)
properties and platelet formation has been understudied. Here, we propose an integrative approach to
investigate emerging concepts related to the role of MK mechanobiological receptors in controlling MK
adhesion to the ECM and platelet production. Our ultimate goal is to understand how specific MK
mechanosensors sense the BM matrix to affect the cellular cytoskeleton, MK properties and, importantly,
platelet level. Building upon our novel findings, Aim 1 explores the new paradigm and hypothesis that distinct
MK cation channels preferentially respond to different BM matrix proteins and inversely impact the MK
cytoskeleton and platelet levels. Experiments will focus on the Piezo family of cation channel mechanosensors,
as compared to the Transient Receptor Potential cation channel subfamily V member 4 mechanosensor. In
recent studies, we found these mechanosensors to have distinct preferences for different matrix proteins and
opposing effects on PPF. Investigations will be carried out using pharmacological approaches as well as newly
generated knockout mice at baseline and in response to challenges, such as myelosuppression or
thrombocytopenia. Encouraged by preliminary studies using human primary MKs, continued studies will
confirm murine findings. Aim 2 delineates mechanisms mediating novel connections between MK
mechanosensors, integrin receptors activation, cytoskeletal changes, and MK mechano-sensitive transcription
factors. This proposal is significant as there is need to identify new and alternative thrombopoietic pathways
and agents that modulate platelet counts. In addition to conceptual innovation, at the technical level we will
analyze new mouse models we developed with deletion of specific mechanosensors in MKs, and will apply
state-of-the-art imaging and measurements under flow to follow cellular processes. Proposed studies are
expected to yield new insights on the role of selective ECM sensing by MKs in controlling the MK cytoskeleton,
adhesion and platelet production, with significant potential to impact our ability to modulate platelet levels.
Terms: <21+ years old><Ablation><Actins><Address><Adhesions><Adult><Adult Human><Affect><Area><Basal Transcription Factor><Basal transcription factor genes><Basement membrane><Biogenesis><Biology><Bleeding><Blood Platelet Count><Blood Platelet Number><Blood Platelet Transfusion><Blood Platelets><Blood Vessels><Blood megakaryocyte><Bone Marrow><Bone Marrow Reticuloendothelial System><Calcium><Cations><Cell Body><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cell-Extracellular Matrix><Cells><Cellular Function><Cellular Matrix><Cellular Mechanotransduction><Cellular Physiology><Cellular Process><Cold-Insoluble Globulins><Collagen><Collagen IV><Collagen Receptors><Collagen Type IV><Cytoskeletal System><Cytoskeleton><DNA Content><DNA Index><DNA Ploidy><Development><ECM><Environment><Extracellular Matrix><Extracellular Matrix Proteins><FN1><Family><Fibronectin 1><Fibronectin Receptor><Fibronectin Receptors><Fibronectins><General Transcription Factor Gene><General Transcription Factors><Generations><Genetic><Goals><Greek><Hemorrhage><Hemostasis><Hemostatic function><Human><IGIV><IV Immunoglobulins><IVIG><Image><Immune globulin IV><In Vitro><Integrins><Integrins Extracellular Matrix><Intracellular Communication and Signaling><Intravenous Antibodies><Intravenous IG><Intravenous Immune Globulin><Intravenous Immunoglobulins><Investigation><KO mice><Knock-out><Knock-out Mice><Knockout><Knockout Mice><Knowledge><LETS Proteins><Large External Transformation-Sensitive Protein><Life><MGDF><MGDF Factor><Marrow><Marrow platelet><Measurement><Mechanical Signal Transduction><Mechanics><Mechanoreceptors><Mechanosensory Transduction><Mediating><Megakaryocyte Colony Stimulating Factor><Megakaryocyte Growth and Development Factor><Megakaryocytes><Megalokaryocyte><Mice><Mice Mammals><Modern Man><Murine><Mus><Myeloproliferative Leukemia Virus Oncogene Ligand><Myelosuppression><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Null Mouse><Opsonic Glycoprotein><Opsonic alpha(2)SB Glycoprotein><Origin of Life><Outcome><Pathology><Pathway interactions><Patients><Phenotype><Piezo 1><Piezo 1 ion channel><Piezo 2><Piezo 2 ion channel><Piezo1><Piezo2><Platelet Count><Platelet Count measurement><Platelet Number><Platelet Transfusion><Platelets><Play><Ploidies><Plts><Production><Property><Proteins><Receptor Activation><Receptor Protein><Reporting><Research><Research Proposals><Role><Signal Transduction><Signal Transduction Systems><Signaling><Structure><Subcellular Process><Testing><Thrombocytes><Thrombocythemia><Thrombocytopenia><Thrombocytopoiesis-Stimulating Factor><Thrombocytopoietin><Thrombopenia><Thrombopoietin><Thrombosis><Transcription Factor Proto-Oncogene><Transcription factor genes><Transfusion><Tubulin><Type IV (Basement Membrane) Collagen><Visualization><adulthood><alpha 2-Surface Binding Glycoprotein><attenuation><biological signal transduction><blood loss><blood product><c-mpl Ligand><chromosome complement><crosslink><developmental><experiment><experimental research><experimental study><experiments><high risk><imaging><in vivo><innovate><innovation><innovative><insight><intracellular skeleton><leukemia><mechanic><mechanical><mechanosensing><mechanotransduction><member><mimetics><mouse model><mpl Ligand><murine model><neuronal><novel><pathway><pharmacologic><preference><pressure><prevent><preventing><receptor><response><side effect><social role><thrombocytosis><thrombotic><thrombotic disease><thrombotic disorder><transcription factor><translational opportunities><translational potential><vascular>