title: Rapamycin increases fetal hemoglobin and ameliorates the nociception phenotype in sickle cell mice.
abstract: Fetal hemoglobin-inducing therapies are disease-modifying and ameliorate the pain phenotype in sickle cell disease (SCD). Rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, increases HbF in erythroid precursor cells in vitro. We hypothesized that rapamycin would increase HbF levels and improve nociception phenotype in SCD mice. We used sine-wave electrical stimulation to examine nocifensive phenotype and evaluate myelinated [2000Hz (Aβ-fiber) and 250Hz (Aδ-fiber)] and unmyelinated (5Hz C-fibers)] sensory fiber function. Rapamycin significantly increased γ-globin mRNA and HbF levels [+2.3% (0.7, 3.9), mean increase (95% confidence interval, CI), p=0.006]. In homozygous (sickling) mice, long- (16 weeks), but not short-term (6 weeks), rapamycin treatment increased 2000Hz and 250Hz current thresholds in a pattern that varied according to sex. In male, but not female mice, rapamycin (compared with vehicle) was associated with increases in 2000Hz [21Units (7, 35), mean difference (95% CI), p=0.009 for sex∗treatment interaction] and 250Hz [9Units (1, 16), p=0.01] current thresholds. In rapamycin-treated homozygotes, HbF levels directly correlated with myelinated [2000Hz(Aβ-fiber, r=0.58, p=0.01) and 250Hz(Aδ-fiber, r=0.6, p=0.01)] but not unmyelinated sensory fiber current thresholds. These findings suggest that in SCD mice, rapamycin increases HbF and modulates current thresholds of myelinated fibers. Therefore, mTOR signaling might be implicated in the pathobiology of SCD.
authors.affiliation: The Sheikh Zayed Institute for Pediatric Surgical Innovation, Division of Pain Medicine, Children's National Health System, School of Medicine and Health Sciences, George Washington University, Washington, DC 20010, United States.
authors.forename: Alfia
authors.initials: A
authors.lastname: Khaibullina
authors.affiliation: The Sheikh Zayed Institute for Pediatric Surgical Innovation, Division of Pain Medicine, Children's National Health System, School of Medicine and Health Sciences, George Washington University, Washington, DC 20010, United States.
authors.forename: Luis E F
authors.initials: LE
authors.lastname: Almeida
authors.affiliation: The Sheikh Zayed Institute for Pediatric Surgical Innovation, Division of Pain Medicine, Children's National Health System, School of Medicine and Health Sciences, George Washington University, Washington, DC 20010, United States.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: The Sheikh Zayed Institute for Pediatric Surgical Innovation, Division of Pain Medicine, Children's National Health System, School of Medicine and Health Sciences, George Washington University, Washington, DC 20010, United States.
authors.forename: Sayuri
authors.initials: S
authors.lastname: Kamimura
authors.affiliation: Laboratory Medicine, Children's Research Institute, Children's National Health System, School of Medicine and Health Sciences, George Washington University, Washington, DC 20010, United States.
authors.forename: Edward C C
authors.initials: EC
authors.lastname: Wong
authors.affiliation: Center for Sickle Cell Disease, Department of Internal Medicine, Howard University, Washington, DC 20001, United States.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Nouraie
authors.affiliation: Hematology Section, Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Irina
authors.initials: I
authors.lastname: Maric
authors.affiliation: The Sheikh Zayed Institute for Pediatric Surgical Innovation, Division of Pain Medicine, Children's National Health System, School of Medicine and Health Sciences, George Washington University, Washington, DC 20010, United States.
authors.forename: Sarah
authors.initials: S
authors.lastname: Albani
authors.affiliation: The Sheikh Zayed Institute for Pediatric Surgical Innovation, Division of Pain Medicine, Children's National Health System, School of Medicine and Health Sciences, George Washington University, Washington, DC 20010, United States.
authors.forename: Julia
authors.initials: J
authors.lastname: Finkel
authors.affiliation: The Sheikh Zayed Institute for Pediatric Surgical Innovation, Division of Pain Medicine, Children's National Health System, School of Medicine and Health Sciences, George Washington University, Washington, DC 20010, United States. Electronic address: zquezado@childrensnational.org.
authors.forename: Zenaide M N
authors.initials: ZM
authors.lastname: Quezado
mesh_terms: D000755:Anemia, Sickle Cell / Q000097:blood* / Q000503:physiopathology*; D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005319:Fetal Hemoglobin / Q000096:biosynthesis* / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D005838:Genotype; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D059225:Nociception / Q000187:drug effects*; D010641:Phenotype; D012684:Sensory Thresholds / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D013697:Thermosensing / Q000187:drug effects
chemical_list: D005319:Fetal Hemoglobin; D020123:Sirolimus
keywords: Fetal hemoglobin; Nociception; Pain; Rapamycin; Sickle cell disease; Sine wave; mTOR