Document text
Principal Investigator: Amanda M Brandow
Organization: MEDICAL COLLEGE OF WISCONSIN
Fiscal Year: 2024
Award: $569,267
Funding agency: National Institute of Neurological Disorders and Stroke
PROJECT SUMMARY/ABSTRACT
The overall goal of this proposed research is to develop a biomarker that prognosticates and correlates with
the clinical expression of pain in sickle cell disease (SCD). Severe, debilitating pain is the most common
complication of SCD, an inherited hemoglobinopathy affecting approximately 100,000 people in the United
States. Despite the known genetic defect, there is significant variability in pain expression in patients with SCD.
Clinically, some patients experience frequent and recurrent pain while others experience pain only
occasionally. Currently, there is no plasma biomarker, linked to pain biology, that can prognosticate patients
who are likely to experience more pain than other patients. The lack of a prognostic biomarker for pain is a
barrier to targeted, personalized pain treatment. SCD is associated with chronic inflammation with elevated
inflammatory mediators (e.g. cytokines, chemokines, lipids) at baseline that increase further during acute pain.
However, the degree of inflammation is likely highly variable among patients. Multiple factors, including
ongoing effects of recurrent vaso-occlusion, ischemia-reperfusion injury, and hemolysis contribute to SCD
inflammation and pain. This project is centered on the concept that pain in SCD is heterogeneous and driven
by a complex milieu of inflammatory effectors and immune regulators. A prognostic biomarker that
quantitatively and comprehensively assesses the combination of these immune effectors and regulators and
correlates with pain in SCD will fill a significant gap in SCD pain research. Ideally, such a biomarker could
provide prognostic data and define inclusion criteria for pain clinical trials of immunomodulatory drugs. The
following aims are proposed for the R61 Phase: 1) Derive the inflammatory index (I.l.com) for pain in patients
with SCD by identifying inflammatory and immune regulatory gene probe sets that will optimally distinguish
healthy controls, patients with SCD in baseline health, and patients with SCD in acute pain and 2) Determine
whether co-expressed gene modules from patients with SCD correlate with clinical pain data and are
concordant with genes included in the I.I.com. Subsequently, the following aims are proposed for the R33
Phase: 1) Determine the reliable and clinically meaningful changes of the I.I.com in patients with SCD and 2)
Investigate the preliminary clinical validity of the I.I.com as a prognostic biomarker for pain in patients with SCD.
Our collaborative and multidisciplinary team brings research expertise in SCD pain biology, inflammation, and
SCD patient-reported outcomes. Our proposed work will refine, replicate and validate the I.I.com as a prognostic
biomarker for SCD pain.
Terms: <Acute Pain><Affect><Analgesia Tests><Assay><B-globin><Bioassay><Biological Assay><Biological Markers><Biological Response Modifiers><Biology><Biomodulators><Blood Plasma><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Chemotactic Cytokines><Chronic><Clinical><Clinical Trials><Complex><Complication><Data><Gene Transcription><Genes><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Goals><Hb SS disease><HbSS disease><Health><Health Care Utilization><Hemoglobin S><Hemoglobin S Disease><Hemoglobin sickle cell disease><Hemoglobin sickle cell disorder><Hemoglobinopathies><Hemolysis><Hereditary><Heterogeneity><Homologous Chemotactic Cytokines><IMiD><Immune><Immune Mediators><Immune Mediators/Modulators><Immune Regulators><Immune modulatory therapeutic><Immune system><Immunes><Immunomodulation><Inflammation><Inflammation Mediators><Inflammatory><Inflammatory Response><Inherited><Intercrines><Intracellular Communication and Signaling><Ischemia-Reperfusion Injury><Link><Lipids><Measures><Mutation><Network Analysis><Nociception Tests><Ontology><Pain><Pain Assessment><Pain Control><Pain Measurement><Pain Research><Pain Therapy><Pain management><Pain measure><Painful><Pathway Analysis><Patient Outcomes Assessments><Patient Reported Measures><Patient Reported Outcomes><Patients><Pattern><Persons><Phase><Plasma><Plasma Serum><Population><Prognostic Marker><RNA Expression><Recurrence><Recurrent><Recurrent pain><Regulator Genes><Reperfusion Damage><Reperfusion Injury><Reporter><Research><Reticuloendothelial System, Serum, Plasma><SIS cytokines><Sickle Cell Anemia><Sickle Hemoglobin><Signal Transduction><Signal Transduction Systems><Signaling><Testing><Training><Transcript><Transcription><Transcriptional Regulatory Elements><United States><Validation><Work><beta Globin><bio-markers><biologic marker><biological signal transduction><biomarker><chemoattractant cytokine><chemokine><clinical heterogeneity><clinical pain><cohort><cytokine><debilitating pain><differential expression><differentially expressed><effective therapy><effective treatment><erythrolysis><experience><genome mutation><genome scale><genome-wide><genomewide><health care service use><health care service utilization><healthcare service use><healthcare service utilization><healthcare utilization><immune modulating agents><immune modulating drug><immune modulating therapeutics><immune modulation><immune modulatory agents><immune modulatory drugs><immune regulation><immunologic reactivity control><immunomodulating agents><immunomodulating drugs><immunomodulator agent><immunomodulator drug><immunomodulator medication><immunomodulator prodrug><immunomodulator therapeutic><immunomodulatory><immunomodulatory agents><immunomodulatory biologics><immunomodulatory drugs><immunomodulatory therapeutics><immunoregulation><immunoregulatory><inclusion criteria><indexing><individual heterogeneity><individual variability><individual variation><inflammatory environment><inflammatory mediator><inflammatory milieu><inter-individual variability><inter-individual variation><interindividual variability><interindividual variation><multidisciplinary><novel><pain assay><pain treatment><prognostic><prognostic biomarker><prognostication><prospective><regulatory gene><response><sickle cell disease><sickle cell disorder><sickle disease><sicklemia><trans acting element><transcriptional differences><validations><β-globin>