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Principal Investigator: Michael P Jankowski
Organization: CINCINNATI CHILDRENS HOSP MED CTR
Fiscal Year: 2024
Award: $475,508
Funding agency: National Institute of Neurological Disorders and Stroke
Abstract: While great deal is understood about mechanisms of sensory transduction from the skin, relatively
little is known about this process from the muscles. As peripheral injuries resulting from repetitive
ischemic/reperfusion (I/R) are a major health issue that affects millions of people in the United States, this gap
in knowledge precludes us from identifying specific therapies for muscle pain or altered cardiovascular
responses to exercise in the context of ischemia. Peripheral I/R occurs in blood disorders such as sickle cell
disease, and in cardiovascular disorders such as peripheral vascular disease. Males and females display
different features of myalgia and exercise pressor reflexes (EPRs) under conditions of reduced peripheral
perfusion. The major goal of this study is to determine the sex specific molecular mechanisms of muscle
afferent sensitization that may underlie the transition from acute to chronic ischemic myalgia. Pilot data in
murine models of repetitive I/R injury suggest that peripheral sensitization in males is regulated by increased
DRG gene expression that is modulated by glial cell line-derived neurotrophic factor (GDNF) family receptor 1
(GFR1) in muscle nociceptors. In females, afferent sensitization, pain-related behaviors and altered EPRs
after repeated I/R injury may be regulated by increased interleukin 1 receptor type 1 (IL1r1) dependent gene
expression. We hypothesize that the prolonged effects of successive I/R injuries are mediated by GDNF
related peripheral sensitization in males and IL1 induced sensitization in females. Aim 1 will determine if
myofiber produced GDNF and DRG upregulation of GFR1, regulate the observed changes in muscle afferent
response properties, pain-related behaviors and altered EPRs after dual I/R in males. We will use muscle fiber
specific GDNF ablation or our novel in vivo siRNA-mediated knockdown of genes in single peripheral nerves in
conjunction with our ex vivo muscle afferent recording preparations or assays of pain-like behaviors and EPRs.
Aim 2 will utilize a similar approach except we will determine if macrophage produced IL1 or DRG
upregulation of IL1r1, regulate the novel changes in female muscle afferents or behaviors after successive I/R.
Finally, Aim 3 will use ex vivo recording and pain-related behavioral analyses to determine if expression
differences in AU-rich element RNA-binding protein 1 (AUF1) or the ras family member, RAN, modulates the
sex specific effects of successive I/R injuries between females versus males. Each of these aims will be
complemented by analysis of DRG and muscle gene expression. The studies outlined here will also provide a
novel direction in muscle neurobiology research that will go well beyond the incremental expansion of current
reports. Results will enable us to identify unique sex dependent mechanisms associated with muscle afferent
sensitization that underlie acute to chronic ischemic myalgia development after I/R injury. This may lead to the
formulation of more appropriate treatments for musculoskeletal pain or altered EPRs associated with ischemia/
reperfusion that target the proper receptor(s), primary afferent subpopulation(s) or peripheral target tissues.
Terms: <Ablation><Aching muscles><Acute><Affect><Afferent Neurons><Allelism Test><Analgesia Tests><Automobile Driving><Basal Transcription Factor><Basal transcription factor genes><Behavior><Behavioral><Blood Diseases><Body Tissues><Cardiovascular><Cardiovascular Body System><Cardiovascular Diseases><Cardiovascular Organ System><Cardiovascular system><Cell Body><Cell Communication and Signaling><Cell Nucleus><Cell Signaling><Cells><Chronic><Complementation Test><Data><Development><Differences between sexes><Differs between sexes><Disease><Disorder><Dorsal Root Ganglia><Electrophysiology><Electrophysiology (science)><Elements><Exercise><Family><Family member><Female><Formulation><GDNF><GDNF gene><Gene Expression><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic Complementation Test><Goals><Growth Agents><Growth Factor><Growth Substances><Hb SS disease><HbSS disease><Health><Heart Vascular><Hematologic Diseases><Hematological Disease><Hematological Disorder><Hemoglobin S Disease><Hemoglobin sickle cell disease><Hemoglobin sickle cell disorder><IL-1 Receptors><IL1 Receptors><Immune><Immunes><Individual><Injury><Interleukin-1 Receptors><Interleukins><Intracellular Communication and Signaling><Ischemia><Ischemia-Reperfusion Injury><Knock-out><Knockout><Knowledge><Macrophage><Mediating><Medulla Spinalis><Mice><Mice Mammals><Molecular><Murine><Mus><Muscle><Muscle Fibers><Muscle Tissue><Muscle discomfort><Muscle pain><Muscle pain/fibrositis><Muscle sorenesss><Musculoskeletal Pain><Myalgia><Myalgic><Myodynia><Myoneuralgia><Myosalgia><Myotubes><Mφ><Nerve><Neurobiology><Neurophysiology / Electrophysiology><Nociception Tests><Nociceptors><Nucleus><Outcome><Pain><Pain Assessment><Pain Measurement><Pain Threshold><Pain Tolerance Level><Pain measure><Painful><Pathway interactions><Perfusion><Peripheral><Peripheral Angiopathies><Peripheral Nerves><Peripheral Vascular Diseases><Peripheral Vascular Disorder><Persistent pain><Persons><Play><Population><Preparation><Prevalence><Process><Property><Proteins Growth Factors><RAS Family Oncogene><RNA Sequences><RNA-Binding Proteins><Receptor Protein><Reflex><Reflex action><Reperfusion Damage><Reperfusion Injury><Reperfusion Therapy><Reporting><Research><Retrovirus Associated Sequence Oncogene><Rhabdomyocyte><Role><Sensory Neurons><Sex Differences><Sexual differences><Short interfering RNA><Sickle Cell Anemia><Signal Transduction><Signal Transduction Systems><Signaling><Skeletal Fiber><Skeletal Muscle><Skeletal Muscle Cell><Skeletal Muscle Fiber><Skeletal Myocytes><Skin><Small Interfering RNA><Source><Spinal Cord><Spinal Ganglia><Testing><Tissues><Trans Test><Transcription Factor Proto-Oncogene><Transcription factor genes><Transgenic Organisms><United States><Up-Regulation><Upregulation><Voluntary Muscle><behavior response><behavioral response><biological signal transduction><blood disorder><cardiovascular disorder><circulatory system><comparing females and males><comparing women and men><complementation analysis><complementation approach><constant pain><cytokine><developmental><dorsal root ganglion><driving><electrophysiological><experience><experiment><experimental research><experimental study><experiments><females compared to males><females compared with males><females versus males><females vs males><glial cell-line derived neurotrophic factor><in vivo><injuries><innovate><innovation><innovative><insight><knock-down><knockdown><lasting pain><male><member><mouse model><murine model><muscular><neurobiological><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><nociceptive neurons><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><on-going pain><ongoing pain><pain assay><pain tolerance><pain-sensing neurons><pain-sensing sensory neurons><pain-sensing somatosensory neurons><pathway><peripheral blood vessel disorder><preparations><prevent><preventing><ras Oncogene><receptor><reperfusion><response><sensory mechanism><sex><sex based differences><sex-dependent differences><sex-related differences><sex-specific differences><siRNA><sickle cell disease><sickle cell disorder><sickle disease><sicklemia><social role><transcription factor><transgenic><women compared to men><women compared with men><women versus men><women vs men>