The overall goal of this project is to understand the signaling mechanisms underlying cell death and survival, using NGF as a model. As a member of the neurotrophin family, NGF regulates the balance between cell survival and death in the nervous system both during development and in adulthood. An imbalance in this regulation can cause a variety of neurodegenerative diseases such as Alzheimer's and Parkinson's. NGF exerts its effects by binding to the cell surface via two distinct types of receptors, TrkA and p75, each capable of eliciting its own signaling response. NGF can either promote neuronal survival or death and this dichotomous action depends on the outcome of the interplay between TrkA and P75. Specifically when JNK, a kinase, is activated by p75, cell die and when suppressed by TrkA, cells live. The primary objective of this application is to investigate the mechanism of TrkA/p75 crosstalk in oligodendrocytes. Our overall hypothesis is that TrkA/p75 crosstalk takes the form of direct, competitive regulation at a particular point in the pathway upstream of JNK. To test this hypothesis, the following specific aims are proposed:
Aim 1 to test whether p75 signaling is required for apoptosis. We will investigate whether oligodendrocytes die in the absence of p75, and whether we can reconstitute the missing effect by introducing back into the p75-/- oligodendrocytes the full-length p75 of the mutant p75 lacking the signaling domain.
Aim 1 1: to test whether Rac functions as the upstream regulator in the JNK pathway and whether TrkA and p75 regulate Rac activity oppositely.
Aim 1 11: to investigate the mechanisms whereby Trk-A mediated PI-3kinase activity suppresses JNK activation. The outcome of this study will result in significant advancement of the current knowledge of NGF signaling by elucidating the basic biochemical mechanisms behind the complex interplay between TrkA and p75. In addition, delineation of the process controlling the precise balance between cell death and survival by NGF may lead to the development of potential therapeutic agents for many degenerative diseases whose etiology may reflect a dis-regulation in this balance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS039472-02
Application #
6394290
Study Section
Special Emphasis Panel (ZRG1-MDCN-2 (01))
Program Officer
Oliver, Eugene J
Project Start
2000-09-30
Project End
2004-08-30
Budget Start
2001-08-31
Budget End
2002-08-30
Support Year
2
Fiscal Year
2001
Total Cost
$330,750
Indirect Cost
Name
Ohio State University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
098987217
City
Columbus
State
OH
Country
United States
Zip Code
43210
Kraemer, B R; Yoon, S O; Carter, B D (2014) The biological functions and signaling mechanisms of the p75 neurotrophin receptor. Handb Exp Pharmacol 220:121-64
Tian, JinBin; Tep, Chhavy; Benedick, Alex et al. (2014) p75 regulates Purkinje cell firing by modulating SK channel activity through Rac1. J Biol Chem 289:31458-72
Limpert, Allison S; Bai, Shujun; Narayan, Malathi et al. (2013) NF-?B forms a complex with the chromatin remodeler BRG1 to regulate Schwann cell differentiation. J Neurosci 33:2388-97
Tian, Jinbin; Tep, Chhavy; Zhu, Michael X et al. (2013) Changes in Spontaneous firing patterns of cerebellar Purkinje cells in p75 knockout mice. Cerebellum 12:300-3
Tep, Chhavy; Kim, Mi Lyang; Opincariu, Laura I et al. (2012) Brain-derived neurotrophic factor (BDNF) induces polarized signaling of small GTPase (Rac1) protein at the onset of Schwann cell myelination through partitioning-defective 3 (Par3) protein. J Biol Chem 287:1600-8
Donnelly, Christopher J; Willis, Dianna E; Xu, Mei et al. (2011) Limited availability of ZBP1 restricts axonal mRNA localization and nerve regeneration capacity. EMBO J 30:4665-77
Kenchappa, Rajappa S; Tep, Chhavy; Korade, Zeljka et al. (2010) p75 neurotrophin receptor-mediated apoptosis in sympathetic neurons involves a biphasic activation of JNK and up-regulation of tumor necrosis factor-alpha-converting enzyme/ADAM17. J Biol Chem 285:20358-68
Harrington, Anthony W; Li, Qi Ming; Tep, Chhavy et al. (2008) The role of Kalirin9 in p75/nogo receptor-mediated RhoA activation in cerebellar granule neurons. J Biol Chem 283:24690-7
Caporali, Andrea; Pani, Elisabetta; Horrevoets, Anton J G et al. (2008) Neurotrophin p75 receptor (p75NTR) promotes endothelial cell apoptosis and inhibits angiogenesis: implications for diabetes-induced impaired neovascularization in ischemic limb muscles. Circ Res 103:e15-26
Li, Qi Ming; Tep, Chhavy; Yune, Tae Y et al. (2007) Opposite regulation of oligodendrocyte apoptosis by JNK3 and Pin1 after spinal cord injury. J Neurosci 27:8395-404

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