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Principal Investigator: Jagadeesh Ramasamy
Organization: UNIVERSITY OF ILLINOIS AT CHICAGO
Fiscal Year: 2022
Award: $455,195
Funding agency: National Center for Complementary and Integrative Health
PROJECT SUMMARY/ABSTRACT
The long-term objective of this proposal is to develop non-opioid novel molecular targets to reduce
the pain suffering and mortality attributed to sickle cell disease (SCD), by identifying to upstream
messengers of acute and chronic pain signaling. Mitochondrial retention in SCD red blood cells
is recognized now to be a major contribution in SCD pathogenesis. However, the downstream
molecular mechanisms related to pain and mitochondrial retention is not investigated. Our
preliminary data suggested that dysregulated autophagy byproducts of Cathepsins, GABARAPs
and synucleins released during lysis of RBCs of SCD red blood cells have potential to trigger pain
episodes in SCD patients. Here, we hypothesized that specific autophagy proteins including
CTSO, CTSW and SNCB along with other known DAMP signaling molecules generated from
SCD RBCs contribute pain in SCD through interaction with pain signaling molecules in
endothelium and neurons. This notion is supported by preliminary data indicating that SCD RBCs
with increased levels of autophagy proteins not only in SCD RBCs but also in plasma compared
to controls. To address this hypothesis, two aims are proposed. The first aim will determine
whether the pain severity of SCD is associated with expression and activity levels of autophagy
proteins in both pediatric and adults SCD patients. The second aim is to determine whether
inhibiting autophagy proteins can reduce pain signaling and pain behaviors in an SCD mouse
model and characterize the molecular interaction of autophagy proteins Synucleins (SNCA,
SNCB), Cathepsins (CTSB, CTSO. CTSW) and GABARAPs (L1 and L2) with pain signaling
molecules. It is anticipated that the result of these studies will make understand the unique
mechanisms of pain in SCD and will ultimately lead to clinical trials to assess new pharmacological
interventions to reduce the need for opiates to manage pain.
Terms: <21+ years old><Abscission><Accident and Emergency department><Active Oxygen><Acute Pain><Address><Adult><Adult Human><Affect><American><Animal Disease Models><Autophagocytosis><B-globin><Binding><Biological Markers><Blood Diseases><Blood Plasma><Blood Precursor Cell><Blood Sample><Blood Vessels><Blood erythrocyte><Blood reticulocyte><Blood specimen><Butanoic Acids><Butyric Acids><CD71><CPSB><CTSB><CTSB gene><Cathepsin B1><Cathepsins><Cathepsins B><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Characteristics><Childhood><Clinic Visits><Clinical><Clinical Trials><Cytolysis><Data><Diffusely basophilic erythrocyte><Disease><Disorder><EC 3.4.22.1><Emergency Department><Emergency room><Endothelial Cells><Endothelium><Erythrocytes><Erythrocytic><Esteroproteases><Excision><Extirpation><Extracellular Space><Frequencies><Gene Expression><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Globin><Goals><Hb SS disease><HbSS disease><Health><Health Care Utilization><Hematologic Diseases><Hematological Disease><Hematological Disorder><Hematopoietic Progenitor Cells><Hematopoietic stem cells><Hemoglobin><Hemoglobin S Disease><Hemoglobin sickle cell disease><Hemoglobin sickle cell disorder><Hemolysis><Hereditary><Hospital Admission><Hospitalization><Individual><Inflammation><Inflammatory><Inherited><Intercellular Space><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Ion Channel Protein><Ion Channel Protein Gene><Lead><Length of Life><Link><Longevity><Lupus Erythematosus Disseminatus><Lysis><Marrow erythrocyte><Marrow reticulocyte><Mice><Mice Mammals><Mitochondria><Mitochondrial DNA><Molecular><Molecular Interaction><Molecular Target><Murine><Mus><Mutation><NAC precursor><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Nociception><Nociceptors><Opiates><Opioid><Oxygen Radicals><PARK1 protein><PARK4 protein><Pain><Pain Control><Pain Therapy><Pain intensity><Pain management><Painful><Pathogenesis><Patients><Pattern><Pb element><Peptidases><Peptide Hydrolases><Persons><Pharmacology><Plasma><Plasma Serum><Point Mutation><Polychromatophilic Erythrocyte><Polymers><Pro-Oxidants><Process><Protease Gene><Proteases><Proteinases><Proteins><Proteolytic Enzymes><Publishing><Reaction><Reactive Oxygen Species><Receptor Protein><Red Blood Cells><Red Cell><Removal><Reporting><Reticulocytes><Reticuloendothelial System, Serum, Plasma><Risk><Role><SLE><SNCA><SNCA protein><Severities><Shapes><Short interfering RNA><Sickle Cell><Sickle Cell Anemia><Signal Transduction><Signal Transduction Systems><Signaling><Signaling Molecule><Small Interfering RNA><Source><Surgical Removal><Systemic Lupus Erythematosus><Systemic Lupus Erythematous><Systemic Lupus Erythmatosus><TFR gene><TFR protein><TFR1><TFRC><TFRC gene><TRFR><Time><Transferrin Receptor><Transferrin Receptor 1><Vanilloid><a-syn><a-synuclein><acute care><adulthood><alpha synuclein><alphaSP22><asyn><autophagy><base><beta Globin><beta-synuclein><bio-markers><biologic marker><biological signal transduction><biomarker><blood corpuscles><blood disorder><blood stem cell><care seeking><chronic pain><disseminated lupus erythematosus><erythrolysis><genome mutation><health care service use><health care service utilization><healthcare service use><healthcare service utilization><healthcare utilization><heavy metal Pb><heavy metal lead><hematopoietic progenitor><hematopoietic stem progenitor cell><hemopoietic progenitor><hemopoietic stem cell><improved><inflammation marker><inflammatory marker><inhibition of autophagy><interventional strategy><life span><lifespan><lipid based nanoparticle><lipid nanoparticle><mitochondrial><mitochondrial autophagy><molecular targeted therapeutics><molecular targeted therapies><molecular targeted treatment><mortality><mouse model><mtDNA><murine model><neuronal><nociceptive><nociceptive neurons><non A-beta component of AD amyloid><non A4 component of amyloid precursor><non-narcotic analgesic><non-opiate analgesic><non-opioid><non-opioid analgesic><non-opioid therapeutics><nonnarcotic analgesics><nonopiate analgesic><nonopioid><nonopioid analgesics><novel><opiate consumption><opiate drug use><opiate intake><opiate use><opioid consumption><opioid drug use><opioid intake><opioid use><overexpress><overexpression><p-Globin><pain behavior><pain reduction><pain signal><pain treatment><pain-sensing neurons><pain-sensing sensory neurons><pain-sensing somatosensory neurons><pediatric><phosphoneuroprotein 14><precursor cell><receptor><reduce pain><resection><siRNA><sickle RBC><sickle cell disease><sickle cell disorder><sickle disease><sickle erythrocyte><sickle red blood cell><sicklemia><sickling><social role><synuclein><systemic lupus erythematosis><targeted biomarker><vascular><vascular inflammation><α-syn><α-synuclein><β-globin>