Document text
Principal Investigator: WENDY M. CAMPANA
Organization: VA SAN DIEGO HEALTHCARE SYSTEM
Fiscal Year: 2024
Funding agency: Veterans Affairs
It is increasingly apparent that Schwann cells (SCs) in the peripheral nervous system (PNS) function as a unit
with neurons to regulate sensory function. When the PNS is injured or stressed, SCs become activated for repair.
This involves dramatic SC phenotypic transformation. If this process is abnormal or inhibited, peripheral nerve
injury may result in chronic debilitating pain, a problem observed in the general population, including numerous
Veterans. Treatment options for chronic neuropathic pain are very limited, and alternatives without addiction are
badly needed. We hypothesize that in response to injury, SC activation is variable from cell to cell so that a
continuum of SC activation states co-exist. We also hypothesize that the SC Repair Program may be augmented
therapeutically to improve outcomes. The major goal of this research project is to determine whether we can
target SC LDL Receptor-related Protein-1 (LRP1), a receptor that we have identified as playing a central role in
the SC Repair Program, to improve pain outcomes following peripheral nerve injury. To accomplish our goals,
three Specific Aims are proposed. In Specific Aim 1, we build on our LC-MS/MS proteomics data obtained from
our previously funded VA Merit Award. We identified an endogenous axon-derived protein, PACSIN 1 as a lead
LRP1 ligand candidate that robustly activated cell signaling pathways associated with the SC Repair Program.
We now seek to identify the SC LRP1 binding domain in PACSIN 1 through site-directed mutagenesis, with the
long-term goal of producing a more druggable pain therapeutic. We then design synthetic PACSIN 1 peptides
that are tested and validated in cell signaling, survival and migration assays associated with the SC Repair
Program. Next, we compare gene expression in SCs after PACSIN 1 transactivation of TrkC, activation by other
LRP1 agonists (EI-tPA, SP16) or direct TrkC activation by neurotrophin-3 (NT-3), with the goal of identifying an
optimized SC LRP1 agonist. In Specific Aim 2, our goal is to test LRP1 agonists in a mouse model of
chemotherapy-induced painful peripheral neuropathy (CIPPN). We build upon our published data showing that
LRP1 agonists reduce acute, inflammatory, and neuropathic pain after traumatic injury, and apply it to paclitaxel
induced painful neuropathy, a commonly used chemotherapeutic agent in the Veteran population. We will
measure several pain modalities in our studies to better understand the experiential pain associated with CIPPN.
We utilize mice with genetic deletion of LRP1 in SCs (scLRP1-/-) generated in my laboratory, to test our
hypothesis that SC LRP1 regulates neuroinflammation and whether LRP1 agonists specifically target SC LRP1.
Finally, in Specific Aim 3, we will test whether LRP1 agonists regulate neuroinflammation induced by CIPPN in
lumbar DRGs. We then utilize single-cell RNASeq to define the cellular landscape of CIPPN nerves and identify
differences in subpopulations of glia and immune cells when PIPN nerves are treated with LRP1 agonists or
when SC LRP1 is absent. We consider this project innovative because we target a known anti-inflammatory
receptor, LRP1 in SCs, instead of neurons to treat chronic pain. This work provides a translational opportunity
to improve chronic pain management in our VA patients.
Terms: <Acceleration><Acute><Acute Pain><Address><Affect><Afferent Neurons><Agonist><American><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Anticonvulsant Agent><Anticonvulsant Drugs><Anticonvulsants><Anticonvulsive Agents><Anticonvulsive Drugs><Anzatax><Apo E Receptor><ApoE Receptor><Apolipoprotein E Receptor><Asotax><Award><Axon><Behavior><Binding><Bristaxol><COVID-19><CV-19><Cancer Survivor><Cancer Treatment><Causality><Cell Body><Cell Communication and Signaling><Cell Function><Cell Migration Assay><Cell Physiology><Cell Process><Cell Signaling><Cell Survival><Cell Viability><Cells><Cellular Function><Cellular Physiology><Cellular Process><Chronic><Conduction-Blocking Anesthetics><Coronavirus Infectious Disease 2019><Cutaneous><Data><Development><Dose><Drugs><Etiology><Event><Funding><GP145-TRKC><Gene Expression><General Population><General Public><Genetic><Genetic Engineering><Genetic Engineering Biotechnology><Genetic Engineering Molecular Biology><Glia><Glial Cells><Goals><Healthcare><Human><Immune><Immunes><Incidence><Inflammatory><Injury><Intracellular Communication and Signaling><Kolliker's reticulum><LDL-Receptor Related Protein 1><Laboratories><Laboratory Research><Lead><Ligands><Link><Local Anesthetics><Low Density Lipoprotein Receptor-Related Protein><Low-Density-Lipoprotein Receptor-Related Protein-1><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Measures><Mediator><Medication><Metabolic><Mice><Mice Mammals><Migration Assay><Modality><Modeling><Modern Man><Molecular><Molecular Interaction><Murine><Mus><NT3 Growth Factor Receptor><NTRK3 Protein><NTRK3 Receptor><Nerve><Nerve Cells><Nerve Fibers><Nerve Growth Factor 2><Nerve Unit><Nervous System Injuries><Nervous System Physiology><Nervous System Trauma><Nervous System damage><Neural Cell><Neurilemma Cell><Neurilemmal Cell><Neurocyte><Neuroglia><Neuroglial Cells><Neurologic function><Neurological Damage><Neurological Injury><Neurological function><Neurological trauma><Neurons><Neurotrophic Tyrosine Kinase Receptor Type 3><Neurotrophin 3><Neurotrophin 3 Receptor><Nociception><Non-neuronal cell><Nonneuronal cell><Opiates><Opioid><PNS Diseases><Paclitaxel><Paclitaxel (Taxol)><Pain><Pain Control><Pain Therapy><Pain management><Painful><Paresthesia><Pathogenesis><Patients><Pb element><Peptides><Peripheral><Peripheral Nerve Diseases><Peripheral Nerves><Peripheral Nervous System><Peripheral Nervous System Diseases><Peripheral Nervous System Disorders><Peripheral Neuropathy><Peripheral nerve injury><Pharmaceutical Preparations><Phenotype><Play><Praxel><Process><Property><Protein-Tyrosine Kinase TRKC><Proteins><Proteomics><Publishing><QOL><Quality of life><R-Series Research Projects><R01 Mechanism><R01 Program><Receptor Protein><Recombinant DNA Technology><Reporting><Research><Research Design><Research Grants><Research Project Grants><Research Projects><Research Resources><Resources><Role><Schwann Cells><Sensory><Sensory Neurons><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Site-Directed Mutagenesis><Site-Specific Mutagenesis><Steroid Compound><Steroids><Stress><Study Type><Subcellular Process><Symptoms><System><TRKC Tyrosine Kinase><Targeted DNA Modification><Targeted Modification><Taxol><Taxol A><Taxol Konzentrat><Testing><Therapeutic><Toxicant exposure><Transactivation><Transmission><Traumatic injury><Veterans><Work><addiction><addictive disorder><afferent nerve><alpha-2-Macroglobulin Receptor><alpha2-Macroglobulin Signaling Receptor><anti-cancer therapy><anti-depressant agent><anti-depressant drugs><anti-depressants><anti-depressive agents><biological signal transduction><cancer therapy><cancer-directed therapy><causation><chemotherapeutic agent><chemotherapy><chronic neuropathic pain><chronic pain><chronic pain control><chronic pain intervention><chronic pain management><chronic pain therapy><chronic pain treatment><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><curative intervention><curative therapeutic><curative therapy><curative treatments><debilitating pain><design><designing><developmental><disease causation><drug/agent><early experience><early onset><genetically engineered><health care><heavy metal Pb><heavy metal lead><hippocampus derived neurotrophic factor><improved><improved outcome><inflammatory pain><injured><injuries><injury response><innovate><innovation><innovative><lab development><laboratory development><military service><military veteran><mouse model><murine model><nerve cement><nerve reconstruction><nerve repair><nervous system function><neural inflammation><neuroinflammation><neuroinflammatory><neuronal><neuropathic pain><neurotrauma><nociceptive><non-narcotic analgesic><non-opiate analgesic><non-opioid><non-opioid analgesic><non-opioid therapeutics><nonnarcotic analgesics><nonopiate analgesic><nonopioid><nonopioid analgesics><novel><pain outcome><pain reduction><pain treatment><pain-related outcome><painful neuropathy><pandemic><pandemic disease><peripheral nerve crush injuries><prevent><preventing><programs><receptor><receptor binding><receptor bound><reduce pain><repair><repaired><research vision><response><response to injury><scRNA-seq><seizure drug><seizure medication><sensory nerve><service programs><side effect><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><study design><toxic exposure><trans-activation><translational opportunities><translational potential><transmission process><treat chronic pain><trkC Protein><trkC Receptor><veteran population>