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
Sleiman, Sama F; Henry, Jeffrey; Al-Haddad, Rami et al. (2016) Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate. Elife 5:
Bowling, Heather; Bhattacharya, Aditi; Zhang, Guoan et al. (2016) BONLAC: A combinatorial proteomic technique to measure stimulus-induced translational profiles in brain slices. Neuropharmacology 100:76-89
Bowling, Heather; Bhattacharya, Aditi; Klann, Eric et al. (2016) Deconstructing brain-derived neurotrophic factor actions in adult brain circuits to bridge an existing informational gap in neuro-cell biology. Neural Regen Res 11:363-7
Mitre, Mariela; Marlin, Bianca J; Schiavo, Jennifer K et al. (2016) A Distributed Network for Social Cognition Enriched for Oxytocin Receptors. J Neurosci 36:2517-35
Mariga, Abigail; Zavadil, Jiri; Ginsberg, Stephen D et al. (2015) Withdrawal of BDNF from hippocampal cultures leads to changes in genes involved in synaptic function. Dev Neurobiol 75:173-92
Mariga, Abigail; Glaser, Juliane; Mathias, Leo et al. (2015) Definition of a Bidirectional Activity-Dependent Pathway Involving BDNF and Narp. Cell Rep 13:1747-56
Kranz, Thorsten M; Goetz, Ray R; Walsh-Messinger, Julie et al. (2015) Rare variants in the neurotrophin signaling pathway implicated in schizophrenia risk. Schizophr Res 168:421-8
Daskalakis, Nikolaos P; De Kloet, Edo Ronald; Yehuda, Rachel et al. (2015) Early Life Stress Effects on Glucocorticoid-BDNF Interplay in the Hippocampus. Front Mol Neurosci 8:68
Anastasia, Agustin; Barker, Phillip A; Chao, Moses V et al. (2015) Detection of p75NTR Trimers: Implications for Receptor Stoichiometry and Activation. J Neurosci 35:11911-20
Zhang, Guoan; Bowling, Heather; Hom, Nancy et al. (2014) In-depth quantitative proteomic analysis of de novo protein synthesis induced by brain-derived neurotrophic factor. J Proteome Res 13:5707-14

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