phone: (310) 825-7264
office: 1024 TLSB
research interests: Neuronal Development and Regeneration: Migration and axon outgrowth
My research focuses on the molecular and cellular interactions that control spinal cord development and regeneration after injury. Currently we study the effects of neuronal migratory errors identified in the reeler spinal cord. The reeler gene encodes Reelin, a secreted glycoprotein that binds the lipoprotein receptors Vldlr and Apoer2, is internalized, and activates a tyrosine kinase cascade that phosphorylates the intracellular adaptor protein Disabled-1 (Dab1). The Reelin-signaling pathway regulates neuronal positioning in the spinal cord in a cell-specific manner; distinct subsets of neurons sustain migratory errors while the others are correctly located. Reelin-signaling pathway mutants have positioning errors in laminae I-II, where nociceptive primary afferents terminate, and in lamina V, a region where multiple nociceptive messages converge on projection neurons that integrate and convey these signals to supraspinal targets. Importantly, there is a functional correlate of the developmental defects in Reelin signaling pathway mutants: an increased sensitivity to heat and a significant reduction in mechanical sensitivity. Our findings indicate that the Reelin signaling pathway is an essential contributor to the normal development of central circuits that underlie thermal and mechanical pain processing. A second focus of the laboratory is to study axon regeneration following complete spinal cord transection. In collaboration with Dr. Edgerton?s lab at UCLA we have completed three extensive studies in which olfactory bulb-derived olfactory ensheathing cells (OECs) were transplanted into the spinal cord after a transection at thoracic level T8. We found that adult spinal rats transplanted with OECs had, relative to control rats receiving medium: 1) improved locomotor performance during hindlimb treadmill stepping, 2) motor evoked potentials induced with transcranial electric stimulation that were lost following re-transection above the original injury, 3) decreased hindlimb withdrawal sensitivity to mechanical stimulation, 4) evidence of supraspinal and propriospinal regeneration, and 5) preservation of neurons near the transection site. To begin to identify the molecular mechanisms underlying the ability of OECs to enhance axonal regeneration, we designed an outgrowth assay using spinal cord myelin as a substrate to mimic the inhibitory glial scar. When dorsal root ganglia (DRG) are co-cultured with OEC on myelin, twice as many neurons generate axons and the average length of the longest axon is almost twice that grown on myelin alone. We used these OEC/DRG co-cultures to show that a factor secreted by OEC, brain-derived neurotrophic factor (BDNF), does indeed contribute to their growth promoting ability.
Thornton, MA, Mehta, MD, Morad, TT, Ingraham, KL, Khankan, RR, Griffis, KG, Yeung, AK, Zhong, H, Roy, RR, Edgerton, VR, Phelps, PE, "Evidence of axon connectivity across a spinal cord transection in rats treated with epidural stimulation and motor training combined with olfactory ensheathing cell transplantation", Expt. Neurol, 309 : 119-133 (2018) [link].
Yvone, G.M., H.H. Zhao-Fleming, J.C. Udeochu, C.L. Chavez-Martinez, A. Wang, M. Hirose- Ikeda, and P.E. Phelps, "Disabled-1 dorsal horn neurons co-express Lmx1b and function in nociceptive circuits", Eur. J. Neurosci, 45 : 733-747 (2017) [link].
Khankan, R.R., K.G. Griffis, J.R. Haggerty-Skeans, H. Zhong, R.R. Roy, V.R. Edgerton, and P.E. Phelps, "Olfactory ensheathing cell transplantation after a complete spinal cord transection mediates neuroprotective and immunomodulatory mechanisms to facilitate regeneration", J. Neurosci, 36 : 6269-6286 (2016) [link].
Fraley, E.R., Z.D. Burkett, N. F. Day, B.A. Schwartz, P.E. Phelps, and S.A. White, "Mice with Dab1 or Vldlr insufficiency exhibit abnormal neonatal vocalization patterns", Scientific Report, 6:25807 : 1-12 (2016) [link].
Ingram, N.T., R.R. Khankan, and P.E. Phelps, "Olfactory ensheathing cells express α7 integrin to mediate their migration on laminin", PLOS One, 11:e0153394 : 1-18 (2016) [link].
Khankan, RR, IB Wanner, and PE Phelps,, "Olfactory ensheathing cell-neurite alignment enhances neurite outgrowth in scar-like cultures", Experimental Neurology, 269 : 93-101 (2015) [link].
Abadesco, A.D., M. Cilluffo, G.M. Yvone, E.M. Carpenter, B.W. Howell, and P.E. Phelps, "Novel Disabled-1-expressing neurons identified in adult brain and spinal cord", European Journal of Neuroscience, 39 : 579-592 (2014) .
Awe, J.P., P.C. Lee, C. Ramathal, A. Vega-Crespo, J. Durruthy-Durruthy, A. Cooper, S. Karumbayaram, W. Lowry, A. Clark, J. Zack, V. Sebastiano, D. Kohn, A. Pyle, M. Martin, G.S. Lipshutz, P.E. Phelps, R. Reijo Pera and J.A. Byrne, "Generation and characterization of transgene-free human induced pluripotent stem cells and conversion to putative clinical-grade status", Stem Cell Research & Therapy, 4 (87): 1-14 (2013) .
Wang, X., A.H.Babayan, A.I. Basbaum and P.E. Phelps, "Loss of the Reelin-signaling pathway differentially disrupts heat, mechanical and chemical nociceptive processing", Neuroscience, 226 : 441-450 (2012) .
Ziegler, M.D., D. Hsu, A. Takeoka, H. Zhong, A. Ramon-Cueto, P.E. Phelps, R.R. Roy, and V.R. Edgerton, "Further evidence of Olfactory Ensheathing Glia facilitating axonal regeneration after a complete spinal cord transection", Experimental Neurology, 229 : 109-119 (2011) .