The proposal has 2 broad goals. The first goal is to elucidate the mechanisms by which neurotrophin interactions with trk and 75kDa neurotrophin receptors (p75NTR) convey retrograde axonal signals to the neuronal cell body. The second goal is to characterize the signal transduction pathways by which p75NTR regulates cell migration and cell death. To test the hypothesis that NGF induces internalization of the NGF/trkA complexes at the axon terminus and transports this endosomal complex back to the neuronal cell body leading to activation of the MAP kinase pathway and other signaling pathways, axonal transport of various components of the NGF signal transduction pathway will be examined in which embryo dorsal root ganglion sensory neurons in compartmentalize cultures (Campenot Chambers). Neuronal differentiated mouse P19 embryonic carcinoma cells, embryonic stem cells (ES) and PC12 cells will be employed to test the hypothesis that neurotrophin/p75NTR enhances apoptotic death of neuronal and other cell types, and to determine whether the NF-KB signaling pathway participate in this regulation. In addition, to test the hypothesis that a major functional ligand of the p75NTR remains to be discovered, the soluble ectodomain of the p75NTR will be used as an affinity probe to extract ligands from tissue extracts, to localize ligands in tissue sections and to screen cDNA libraries expressed in mammalian cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS033200-04
Application #
2488188
Study Section
Neurology C Study Section (NEUC)
Program Officer
Leblanc, Gabrielle G
Project Start
1995-01-01
Project End
2000-12-31
Budget Start
1998-01-14
Budget End
1998-12-31
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Washington
Department
Physiology
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Hatch, Nan E; Hudson, Mark; Seto, Marianne L et al. (2006) Intracellular retention, degradation, and signaling of glycosylation-deficient FGFR2 and craniosynostosis syndrome-associated FGFR2C278F. J Biol Chem 281:27292-305
Kanning, Kevin C; Hudson, Mark; Amieux, Paul S et al. (2003) Proteolytic processing of the p75 neurotrophin receptor and two homologs generates C-terminal fragments with signaling capability. J Neurosci 23:5425-36
Burke, Melanie A; Bothwell, Mark (2003) p75 neurotrophin receptor mediates neurotrophin activation of NF-kappa B and induction of iNOS expression in P19 neurons. J Neurobiol 55:191-203
Iwamoto, Satori; Burrows, Robert C; Kalina, Robert E et al. (2002) Immunophenotypic differences between uveal and cutaneous melanomas. Arch Ophthalmol 120:466-70
Iwamoto, Satori; Burrows, Robert C; Grossniklaus, Hans E et al. (2002) Immunophenotype of conjunctival melanomas: comparisons with uveal and cutaneous melanomas. Arch Ophthalmol 120:1625-9
Hutson, L D; Bothwell, M (2001) Expression and function of Xenopus laevis p75(NTR) suggest evolution of developmental regulatory mechanisms. J Neurobiol 49:79-98
Iwamoto, S; Burrows, R C; Agoff, S N et al. (2001) The p75 neurotrophin receptor, relative to other Schwann cell and melanoma markers, is abundantly Expressed in spindled melanomas. Am J Dermatopathol 23:288-94
Gunther, E C; von Bartheld, C S; Goodman, L J et al. (2000) The G-protein inhibitor, pertussis toxin, inhibits the secretion of brain-derived neurotrophic factor. Neuroscience 100:569-79
Yuen, E C; Gunther, E C; Bothwell, M (2000) Nitric oxide activation of TrkB through peroxynitrite. Neuroreport 11:3593-7
Iwamoto, S; Burrows, R C; Born, D E et al. (2000) The application of direct immunofluorescence to intraoperative neurosurgical diagnosis. Biomol Eng 17:17-22