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Principal Investigator: Elizabeth Anne Middleton
Organization: UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
Fiscal Year: 2024
Award: $166,525
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY/ABSTRACT
This is an application for a K08 award for Dr. Elizabeth Middleton, a pulmonary and critical care physician at
the University of Utah. Dr. Middleton is establishing herself as a young investigator in translational research of
biological mechanisms driving the pathophysiology of sepsis. Her long-term goal is identification of new
therapeutic targets to advance the care of patients suffering with sepsis so they have longer and have
improved quality of life. The role of platelets in inflammation and infection is poorly understood. She is
proposing to investigate the contribution of the megakaryocytes (the platelet parent cell) and platelets, and how
they impact a patient’s response to sepsis. This K08 will provide Dr. Middleton with the support necessary to
accomplish the following goals: 1) gain expertise in megakaryocyte (MK) biology, gene expression, and
functional assessments, 2) to increase knowledge of platelet FcγRIIA biology and function through use of
humanized transgenic mouse model, 3) to develop the skills and toolsets to dissect intracellular platelet
signaling events, 4) expand skills to independently lead and manage a translational research program. To
achieve these goals, Dr. Middleton has assembled a mentoring team comprising a primary mentor, Dr.
Matthew Rondina, an established physician-investigator and leader in the field of platelet biology in immune
responses and inflammation, and 4 advisors who are leaders in the fields of megakaryocyte gene expression,
biology and function, translational research in sepsis and acute respiratory distress syndrome, and genetically
altered murine research.
The primary treatment for sepsis is early recognition and hemodynamic resuscitation, antibiotics and
supportive care. Despite hospital-based systems to detect the onset of sepsis, it continues to carry significant
mortality, short- and long-term morbidity. Dr. Middleton’s research focuses on the study of a platelet immune
receptor, Fc fragment of IgG receptor IIA (FcγRIIA), which is positioned at the cross-roads hemostatic,
immune, and inflammatory continuum. Dr. Middleton will (Aim 1) determine how platelet FcγRIIA expression is
increased in sepsis; (Aim 2) determine if increased platelet FcγRIIA during sepsis causes hyperactivation,
thrombosis, and mortality. In Aim 1, Dr. Middleton will investigate the inflammatory agonists that drive
increases in platelet FcγRIIA and track the expression of this receptor from the megakaryocyte to circulating
platelets. In Aim 2, Dr. Middleton will interrogate whether the increased platelet FcγRIIA contributes to risk of
thrombosis and short-term mortality associated with sepsis. This research will prepare Dr. Middleton to design
and implement a research program with clinical applicability to inform future therapies for sepsis.
Terms: <Acute><Affinity><Age><Agonist><Animal Model><Animal Models and Related Studies><Antibiotic Agents><Antibiotic Drugs><Antibiotics><Automobile Driving><Award><Biology><Blood Platelet Count><Blood Platelet Number><Blood Platelets><Blood megakaryocyte><CLP model><CLP mouse model><Cecal ligation perforation><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Clinical><Clinical Trials><Complex><Critical Care><Data><Dysfunction><Event><Failure><Fc Fragments><Fc Immunoglobulins><Fc Receptor><Functional disorder><Future><Gene Expression><Gene Transcription><Genetic Transcription><Goals><Grant><Hemostasis><Hemostatic Agents><Hemostatic function><Hemostatics><Hospitals><Human><Hyperactivity><IACUC><IRB><IRBs><IgG Receptors><Immune><Immune response><Immunes><Immunoglobulin G Receptor><Immunologic Receptors><Immunological Receptors><Immunological response><Infection><Inflammation><Inflammatory><Institutional Animal Care and Use Committee><Institutional Review Boards><Integrins><Integrins Extracellular Matrix><Intracellular Communication and Signaling><Investigators><Knowledge><Laboratories><Lead><Lung><Lung Respiratory System><Marrow platelet><Megakaryocytes><Megalokaryocyte><Mentors><Messenger RNA><Mice><Mice Mammals><Miscellaneous Antibiotic><Modern Man><Molecular Fingerprinting><Molecular Profiling><Morbidity><Morbidity - disease rate><Murine><Mus><Outcome><Parents><Patient Care><Patient Care Delivery><Pb element><Physicians><Physiopathology><Platelet Count><Platelet Count measurement><Platelet Number><Platelets><Population><Position><Positioning Attribute><Proteins><Protocol><Protocols documentation><Publishing><QOL><Quality of life><RNA Expression><Regulation><Research><Research Personnel><Researchers><Resuscitation><Ribo-seq><Risk><Role><Scientist><Sepsis><Sepsis and ARDS><Signal Transduction><Signal Transduction Systems><Signaling><Stimulus><Supportive Therapy><Supportive care><Syndrome><System><Techniques><Testing><Therapeutic><Thrombocytes><Thrombosis><Time><Transcript><Transcription><Transcription Regulation><Transcriptional Control><Transcriptional Regulation><Transgenic Mice><Transgenic Organisms><Translational Regulation><Translational Research><Translational Research Enterprise><Translational Science><Translations><Tyrosine><Universities><Up-Regulation><Upregulation><Utah><Work><acute respiratory distress syndrome caused by sepsis><adverse consequence><adverse outcome><ages><antibody receptor><biological research><biological signal transduction><blood infection><bloodstream infection><care for patients><care of patients><caring for patients><cecal ligation and perforation><cecal ligation and puncture><cecal ligation puncture><cecum ligation and puncture><cecum ligation puncture><clinical applicability><clinical application><death risk><design><designing><driving><gamma Fc Receptors><global gene expression><global transcription profile><heavy metal Pb><heavy metal lead><hemodynamics><host response><immune receptor><immune system response><immunoresponse><improved><innovate><innovation><innovative><mRNA><mRNA Expression><model of animal><molecular profile><molecular signature><mortality><mortality risk><mouse model><murine model><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><parent><pathogen><pathophysiology><patient response><patient specific response><pharmacologic><platelet function><programs><protein expression><pulmonary><receptor expression><response><responsive patient><ribosome footprint profiling><ribosome profiling><risk minimization><sepsis ARDS><sepsis acute respiratory distress syndrome><sepsis and acute respiratory distress syndrome><sepsis associated acute respiratory distress syndrome><sepsis induced ARDS><sepsis induced acute respiratory distress syndrome><sepsis patients><sepsis related acute respiratory distress syndrome><septic><septic patients><skills><social role><thrombotic disease><thrombotic disorder><transcriptome><transgenic><translation><translation research><translation research enterprise><translational investigation><translational research program><treatment effect>