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Principal Investigator: Jing Pan
Organization: UNIVERSITY OF FLORIDA
Fiscal Year: 2024
Award: $158,008
Funding agency: National Institute of Biomedical Imaging and Bioengineering
Project Summary/Abstract
Sepsis is one of the major healthcare problems in the United States with an annual patient care cost approaching $23
billion. Despite a substantial decrease in inpatient mortality over the past 15 years, the current epidemiology indicates a
disturbing increase in the number of sepsis survivors who develop a chronic critical illness (CCI) phenotype featuring
prolonged ICU stay and poor long-term outcomes. The most important clinical challenge in sepsis care today is identifying
early and continuously monitor those patients with a high risk of either dying or developing CCI. Previous clinical studies
show unstable sepsis patients have distinct immunologic subtypes (endotype) defined by the level and fluctuation of
circulating immunomodulators over time. Unfortunately, current standard immunoassays (e.g. ELISA) provide only
intermittent sampling of biomarker levels with a sample-to-result time of several hours to days, which is insufficient for
timely clinical decision making using immune endotypes. The long-term goal of this research is to develop improved
bioanalytical tools for predicting clinical trajectory and tailoring medical intervention based on sepsis patient’s individual
pathophysiologic endotype. The overall objective in this application is to develop a biosensor platform that addresses the
analytical needs of immunologic endotyping in sepsis patient care. A major technical challenge in the real-time monitoring
of biomolecules is achieving fast response while maintaining low limit of detection (LOD). To resolve this conflict, the
application proposes to adopt the thermal cycling process used in PCR and repurpose it for real-time protein detection. We
will develop affinity reagents with temperature-selective binding properties (aim 1). This novel affinity reagent will be
integrated with an ultrafast photothermal cycling sensor platform to enable sensitive and frequent biomolecular monitoring
(aim 2). In aim 1 we will use in vitro selection to identify binders with temperature-sensitive affinity towards a 3- biomarker
panel containing two immune-modulating proteins (i.e. IL-6 and sPD-L1) and a tissue injury indicator thrombomodulin.
The optimum temperature range and binding curve for the selected reagents will be characterized. In aim 2 we will develop
a sensor platform capable of frequent, multiplexed detection of IL-6, sPD-L1 and thrombomodulin in human whole blood.
The research proposed is innovative because it combines novel affinity reagents and sensing mechanisms to reconcile the
slow off-rate needed for sensitive detection and the fast off-rate needed for fast assay time. The proposed technology is
significant because it is generally applicable to many diseases associated with uncontrolled, systematic inflammatory
response, such as the management of severe COVID-19 patients and treatment for patients with cytokine release syndrome
after immunotherapy. Furthermore, the successful completion of this project will form the basis for future studies, such as
the clinical study on immunologic endotypes diagnostic values at different stages of sepsis, the pharmacokinetics of novel
therapeutics, and the closed-loop intervention of chronic diseases.
Terms: <Address><Adopted><Affinity><Antibodies><Architecture><Assay><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><B7-H1><B7H1><BCDF><BSF-2><BSF2><Binding><Bioassay><Biochemical><Biologic Models><Biologic Sciences><Biological Assay><Biological Markers><Biological Models><Biological Sciences><Biomedical Engineering><Bioscience><Biosensor><Blood><Blood Cells><Blood Reticuloendothelial System><CD274><COVID infected patient><COVID patient><COVID positive patient><COVID-19 infected patient><COVID-19 patient><COVID-19 positive patient><COVID-19 therapy><COVID-19 treatment><COVID19 patient><COVID19 positive patient><Caring><Cell Communication and Signaling><Cell Signaling><Cessation of life><Chronic><Chronic Disease><Chronic Illness><Clinical><Clinical Research><Clinical Study><Cohort Studies><Concurrent Studies><Critical Care><Critical Illness><Critically Ill><Data><Data Bases><Databases><Death><Detection><Development><Devices><Diagnosis><Diagnostic><Disease><Disease Management><Disease Progression><Disorder><Disorder Management><Dissociation><Drug Kinetics><ELISA><Early identification><Engineering><Engineering / Architecture><Enzyme-Linked Immunosorbent Assay><Epidemiology><Equilibrium><Event><Fluorescence><Future><Goals><HPGF><Health Care Systems><Healthcare><Healthcare Systems><Heating><Hepatocyte-Stimulating Factor><Hospitals><Hour><Human><Hybridoma Growth Factor><IFN-beta 2><IFNB2><IL-6><IL6 Protein><Immune><Immune Diseases><Immune Disorders><Immune Dysfunction><Immune System Diseases><Immune System Disorder><Immune System Dysfunction><Immune System and Related Disorders><Immune mediated therapy><Immune response><Immunes><Immunoassay><Immunochemical Immunologic><Immunodeficiency and Immunosuppression Disorders><Immunologic><Immunologic Diseases><Immunologic Subtyping><Immunological><Immunological Diseases><Immunological Dysfunction><Immunological System Dysfunction><Immunological response><Immunologically><Immunologically Directed Therapy><Immunologics><Immunomodulation><Immunomodulators><Immunophenotyping><Immunotherapy><In Vitro><Incubated><Individual><Inflammatory Response><Inpatients><Interleukin-6><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Knowledge><Libraries><Life Sciences><MGI-2><Measurement><Medical><Microfluidic Device><Microfluidic Lab-On-A-Chip><Microfluidic Microchips><Mission><Model System><Modern Man><Molecular><Molecular Interaction><Monitor><Morbidity><Morbidity - disease rate><Myeloid Differentiation-Inducing Protein><NIBIB><National Institute of Biomedical Imaging and Bioengineering><Oligo><Oligonucleotides><Outcome><PD-L1><PDL-1><PDL1><Patient Care><Patient Care Delivery><Patients><Performance><Peripheral Blood Cell><Pharmacokinetics><Phenotype><Physicians><Plasmacytoma Growth Factor><Procedures><Process><Programmed Cell Death 1 Ligand 1><Programmed Death Ligand 1><Property><Proteins><Public Health><Reagent><Recycling><Research><SARS-CoV-2 infected patient><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 therapy><SARS-CoV-2 treatment><Sampling><Scaffolding Protein><Scheme><Science><Scientist><Sepsis><Septic Shock><Signal Transduction><Signal Transduction Systems><Signaling><Surface><Survivors><Technology><Temperature><Therapeutic><Thrombase><Thrombin><Thrombomodulin><Time><Transducers><United States><Whole Blood><Work><Yeasts><absorption><aptamer><balance><balance function><bio-engineered><bio-engineers><bio-markers><bioengineering><biologic marker><biological engineering><biological sensor><biological signal transduction><biomarker><biomarker array><biomarker panel><blood infection><bloodstream infection><care costs><care for patients><care of patients><caring for patients><chronic disorder><clinical decision-making><clinical predictors><conflict resolution><coronavirus disease 2019 infected patient><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 therapy><coronavirus disease 2019 treatment><coronavirus disease infected patient><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease-19 patient><coronavirus patient><cytokine release syndrome><cytokine storm><data base><design><designing><detection limit><developmental><diagnostic ability><diagnostic capability><diagnostic power><diagnostic utility><diagnostic value><enzyme linked immunoassay><epidemiologic><epidemiological><evidence base><experience><fibrinogenase><health care><high risk><host response><immune modulation><immune modulators><immune regulation><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunologic reactivity control><immunomodulatory><immunophenotype><immunoregulation><immunoregulatory><immunoresponse><improved><individual patient><injury response><injury to tissue><innovate><innovation><innovative><interferon beta 2><interventional strategy><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><marker panel><microfluidic chip><mortality><multiplex detection><nano particle><nano-sized particle><nanoparticle><nanosized particle><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><oligos><operation><operations><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><plasmonics><predictive tools><programmed cell death ligand 1><programmed cell death protein ligand 1><protein death-ligand 1><rate of change><real time monitoring><realtime monitoring><response><response to injury><response to therapy><response to treatment><scaffold><scaffolding><sensor><sepsis patients><septic patients><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 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><severe acute respiratory syndrome coronavirus 2 therapy><severe acute respiratory syndrome coronavirus 2 treatment><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><tech development><technology development><therapeutic response><therapy response><tissue injury><treat COVID-19><treat SARS-CoV-2><treat coronavirus disease 2019><treat severe acute respiratory syndrome coronavirus 2><treatment response><treatment responsiveness>