Neurotrophins, such as NGF and BDNF, are prominent regulators of neuronal survival, growth and differentiation during development of the vertebrate nervous system. They also play an important role in higher order functions, such as pain, addiction, mood disorders and learning and memory. A major problem in the field is to explain how neurotrophins are able to carry out these diverse activities through receptor signaling. The actions of neurotrophins are dictated by two cell surface receptors, Trk tyrosine kinases and the p75 receptor. We are interested in the role of Trk receptor signaling in dictating neuronal responsiveness by neurotrophins. In the next grant period, we will focus upon a multifunctional scaffold protein called ARMS/Kidins220, which is a principal substrate of Trk receptors. This protein is heavily tyrosine phosphorylated by neurotrophins and plays a critical role in the branching of cortical and hippocampal dendrites;in the turnover of cortical spines;and also in modulating basal synaptic transmission. The mechanisms by which ARMS/Kidins220 are involved in neurodegeneration in the entorhinal cortex, as well as receptor tyrosine kinase signaling and interactions with glutamate receptors will be studied. Our investigation is directly relevant to understanding the mechanism of trophic factors and their roles in neurodegenerative diseases, such as amyotrophic lateral sclerosis, Huntington's and Alzheimer's diseases, as well as psychiatric disorders, such as anxiety and depression.

Public Health Relevance

Neurotrophic factors, such as Brain-Derived Neurotrophic Factor (BDNF), are activity dependent proteins that are responsible for neuron survival and differentiation. They also act to influence higher order activities, such as learning, memory and behavior. An unexplored area is how BDNF signals through its receptors in a specific manner to modulate these diverse activities. The signal transduction mechanism of neurotrophins and their receptors will help to understand their roles during development and in the treatment of neurodegenerative diseases, such as Alzheimer's and Huntington's diseases, and psychiatric and addictive disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS021072-28
Application #
8658854
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Mamounas, Laura
Project Start
1985-04-01
Project End
2016-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
28
Fiscal Year
2014
Total Cost
$365,990
Indirect Cost
$149,428
Name
New York University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Deinhardt, Katrin; Chao, Moses V (2014) Shaping neurons: Long and short range effects of mature and proBDNF signalling upon neuronal structure. Neuropharmacology 76 Pt C:603-9
Jeanneteau, F; Chao, M V (2013) Are BDNF and glucocorticoid activities calibrated? Neuroscience 239:173-95
Scharfman, Helen E; Chao, Moses V (2013) The entorhinal cortex and neurotrophin signaling in Alzheimer's disease and other disorders. Cogn Neurosci 4:123-35
Anastasia, Agustin; Deinhardt, Katrin; Chao, Moses V et al. (2013) Val66Met polymorphism of BDNF alters prodomain structure to induce neuronal growth cone retraction. Nat Commun 4:2490
Shroff, Seema; Mierzwa, Amanda; Scherer, Steven S et al. (2011) Paranodal permeability in "myelin mutants". Glia 59:1447-57
Duffy, Aine M; Schaner, Michael J; Wu, Synphen H et al. (2011) A selective role for ARMS/Kidins220 scaffold protein in spatial memory and trophic support of entorhinal and frontal cortical neurons. Exp Neurol 229:409-20
Wu, Synphen H; Arévalo, Juan Carlos; Neubrand, Veronika E et al. (2010) The ankyrin repeat-rich membrane spanning (ARMS)/Kidins220 scaffold protein is regulated by activity-dependent calpain proteolysis and modulates synaptic plasticity. J Biol Chem 285:40472-8
Chao, Moses V (2010) Increasing the specificity of neurotrophic factors. Proc Natl Acad Sci U S A 107:13565-6
Jeanneteau, Freddy; Deinhardt, Katrin; Miyoshi, Goichi et al. (2010) The MAP kinase phosphatase MKP-1 regulates BDNF-induced axon branching. Nat Neurosci 13:1373-9
Ninan, Ipe; Bath, Kevin G; Dagar, Karishma et al. (2010) The BDNF Val66Met polymorphism impairs NMDA receptor-dependent synaptic plasticity in the hippocampus. J Neurosci 30:8866-70

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