The overall goal of our research is to understand the interaction of signal transduction cascades which mediate neuronal development and survival. Both neurotrophins and neuronal activity induce the transcription of genes crucial for neuronal survival. However, the mechanisms by which these pathways interact to modulate gene expression are unclear. Recent results indicate that cross-talk exists between neurotrophin- and activity- induced cascades. Olfactory receptor neurons (ORNs) are used as a model for these studies: they depend upon both activity and neurotrophins (brain-derived neurotrophic factor, BDNF) for survival ORNs are continually replaced during life from a maintained population of precursors, providing us with an excellent opportunity to study neurogenesis Our data show that both odorants and neurotrophins activate the Ras-MAPK cascade and induce CREB phosphorylation. Odorants increase cAMP, cGMP, inositol phosphates, and intracellular calcium levels. Therefore, any of these pathways may interact with the neurotrophin-induced cascade. We hypothesize that odorant-induced signals modulate neurotrophin-activated cascades to influence neuronal survival. Primary cultures of ORNs in which odorant and neurotrophin signaling is preserved, and genetic models in which activity of neurotrophin signal transduction is interrupted, are utilized in this proposal.
In Aim 1, we will use primary cultures and activators/inhibitors of odorant-induced signaling pathways to characterize the interactions of odorant and BDNF-activated cascades. We will determine dose-response curves and time courses for CREB activation by odorants and BDNF; define the role of the odorant-induced cAMP pathway in CREB activation; and identify the role of other odorant-induced signaling pathways in CREB activation.
In Aim 2, we will define the steps in the Ras-MAPK pathway through which odorant-activated cascades interact with the neurotrophin pathway.
In Aim 3, we will determine which signaling paths are important to ORN survival. Odorants may activate multiple pathways, but not all may be relevant to survival. Genetic models in which either activity (OCNC1 null mice) or BDNF signaling (BDNF null mice) is interrupted are used to define the physiological role of these pathways in survival. Understanding these mechanisms is essential to our ability to manipulate that process.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS039657-02S1
Application #
6447351
Study Section
Special Emphasis Panel (ZRG1 (01))
Program Officer
Leblanc, Gabrielle G
Project Start
2000-01-01
Project End
2004-12-31
Budget Start
2001-01-01
Budget End
2001-12-31
Support Year
2
Fiscal Year
2001
Total Cost
$33,000
Indirect Cost
Name
Johns Hopkins University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
El Meskini, Rajaa; Crabtree, Kelli L; Cline, Laura B et al. (2007) ATP7A (Menkes protein) functions in axonal targeting and synaptogenesis. Mol Cell Neurosci 34:409-21
Simpson, P Jeanette; Moon, Cheil; Kleman, Amy M et al. (2007) Progressive and inhibitory cell cycle proteins act simultaneously to regulate neurotrophin-mediated proliferation and maturation of neuronal precursors. Cell Cycle 6:1077-89
Niciu, M J; Ma, X-M; El Meskini, R et al. (2006) Developmental changes in the expression of ATP7A during a critical period in postnatal neurodevelopment. Neuroscience 139:947-64
Chen, Jijun; Tu, Yajun; Connolly, Erin C et al. (2005) Heme oxygenase-2 protects against glutathione depletion-induced neuronal apoptosis mediated by bilirubin and cyclic GMP. Curr Neurovasc Res 2:121-31
Chen, Jijun; Tu, Yajun; Moon, Cheil et al. (2004) The localization of neuronal nitric oxide synthase may influence its role in neuronal precursor proliferation and synaptic maintenance. Dev Biol 269:165-82
Simpson, P Jeanette; Wang, Eugene; Moon, Cheil et al. (2003) Neurotrophin-3 signaling maintains maturational homeostasis between neuronal populations in the olfactory epithelium. Mol Cell Neurosci 24:858-74
Boehning, Darren; Moon, Cheil; Sharma, Sumit et al. (2003) Carbon monoxide neurotransmission activated by CK2 phosphorylation of heme oxygenase-2. Neuron 40:129-37
Chen, Jijun; Tu, Yajun; Moon, Cheil et al. (2003) Heme oxygenase-1 and heme oxygenase-2 have distinct roles in the proliferation and survival of olfactory receptor neurons mediated by cGMP and bilirubin, respectively. J Neurochem 85:1247-61
Simpson, P Jeanette; Miller, Ian; Moon, Cheil et al. (2002) Atrial natriuretic peptide type C induces a cell-cycle switch from proliferation to differentiation in brain-derived neurotrophic factor- or nerve growth factor-primed olfactory receptor neurons. J Neurosci 22:5536-51
Sung, Young K; Moon, Cheil; Yoo, Joo-Yeon et al. (2002) Plunc, a member of the secretory gland protein family, is up-regulated in nasal respiratory epithelium after olfactory bulbectomy. J Biol Chem 277:12762-9