Age related functional decline of nervous system is consistently observed, the sequence of causative molecular events for age related functional decline is unknown. This proposal focuses on possible roles of transmembrane Neuregulin-1 (Nrg-1) may have on this aging process. Our recent work revealed: (a) the cytoplasmic domain of Neuregulin-1 (Nrg-ICD) can translocate into the nucleus and regulate gene expression including that of PSD-95 and apoptotic genes; (b) Nrg-ICD regulates PSD-95 expression by binding to a transcription factor, Eos, and (c) during aging there is a correlation between nuclear translocation of Nrg-ICD and up-regulation of PSD-95 and BAK, a pro-apoptotic gene. The general hypothesis is that NRG-1 plays an essential role in age related neuronal changes. To test this hypothesis, we have made a conditional tissue-specific transgenic mouse model, which conditionally expresses Nrg-1 in several specific regions including hippocampus, spiral ganglion neurons, and outer-hair cells. By taking advantage of this mouse model, we will examine three related issues: (1) whether conditional overexpression of Nrg-1 in adult mice can alter age related hearing loss; (2) whether a conditional overexpression of Nrg-1 in adult mice can alter age related neuronal changes in hippocampus; (3) whether caloric restriction, the most effective way to delay the aging process, affects the role of Nrg-1 signaling pathways on age related neuronal changes. The ultimate goal of our research is to develop methods for prevention and treatment of age related functional decline of nervous system based on identifying molecular candidates involved in the aging process ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG024250-01
Application #
6812950
Study Section
Neurodegeneration and Biology of Glia Study Section (NDBG)
Program Officer
Finkelstein, Judith A
Project Start
2004-09-30
Project End
2009-07-31
Budget Start
2004-09-30
Budget End
2005-07-31
Support Year
1
Fiscal Year
2004
Total Cost
$311,392
Indirect Cost
Name
Washington University
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Jin, David; Ohlemiller, Kevin K; Lei, Debin et al. (2011) Age-related neuronal loss in the cochlea is not delayed by synaptic modulation. Neurobiol Aging 32:2321.e13-23
Perez, Philip; Bao, Jianxin (2011) Why do hair cells and spiral ganglion neurons in the cochlea die during aging? Aging Dis 2:231-41
Lin, Zhaoyu; Perez, Philip; Lei, Debin et al. (2011) Two-phase analysis of molecular pathways underlying induced pluripotent stem cell induction. Stem Cells 29:1963-74
Shen, Haiyan; Lin, Zhaoyu; Lei, Debin et al. (2011) Old mice lacking high-affinity nicotine receptors resist acoustic trauma. Hear Res 277:184-91
Lei, Debin; Gao, Xia; Perez, Philip et al. (2011) Anti-epileptic drugs delay age-related loss of spiral ganglion neurons via T-type calcium channel. Hear Res 278:106-12
Bao, Jianxin; Ohlemiller, Kevin K (2010) Age-related loss of spiral ganglion neurons. Hear Res 264:93-7
Xu, Jan; Chen, Shawei; Chen, Hong et al. (2009) STAT5 mediates antiapoptotic effects of methylprednisolone on oligodendrocytes. J Neurosci 29:2022-6
Wildburger, Norelle C; Lin-Ye, Avary; Baird, Michelle A et al. (2009) Neuroprotective effects of blockers for T-type calcium channels. Mol Neurodegener 4:44
Jin, David Xu; Lin, Zhaoyu; Lei, Debin et al. (2009) The role of glucocorticoids for spiral ganglion neuron survival. Brain Res 1277:3-11
Shen, Haiyan; Zhang, Baoping; Shin, June-Ho et al. (2007) Prophylactic and therapeutic functions of T-type calcium blockers against noise-induced hearing loss. Hear Res 226:52-60

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