The Program Project hypothesizes that the processes of progenitor proliferation, neural differentiation, axon extension and synapse formation are regulated by neuron-neuron and neuron-glial interactions. These cell-cell interactions, in turn, are mediated through the actions of multiple intercellular and intracellular signals that impact seemingly unrelated developmental events. Our studies will elucidate molecules and mechanisms that regulate proliferation, survival, differentiation and synaptogenesis in the developing brain. They focus on the roles of BDNF and Eph family members and lead us to increased understanding of how to effect brain repair and regeneration. Importantly, the studies move from the culture dish, to the developing brain in vivo. Moreover, they extend the work to analysis of a neurotherapeutic molecule used for women of childbearing age. To achieve our goals. Project 1 will examine mechanisms by which the anticonvulsant, valproic acid affects development of neurons and glia, ranging from proliferation control to differentiation, neurotrophin signaling and behavioral consequences. Project 2 will explore an emerging field of signal interaction between Eph and Trk family receptors. Project 3 will define mechanisms underlying synaptic plasticity by examining the roles of cytoskeletal structures in transmitter receptor trafficking and spine enlargement/formation and shrinkage and their regulation by intracellular kinases and BDNF. Project 4 will explore mechanisms underlying the processing and release of pro- and mature isoforms of BDNF from neurons. Project 5 will examine roles played by astrocytes in providing BDNF to effect development and maintenance of proximate neurons and oligodendrocytes.

Public Health Relevance

This program explore mechanisms impacting BDNF release and the building of neuronal connections. Moreover, it examines effects of a neurotherapeutic, valproic acid, given to women of childbearing age. Disregulation of these processes is a significant component of neurodevelopmental pathologies. Further, abnormal fronto-limbic connectivity underlies conditions such as anxiety and autism. The mechanisms established in this program are likely to yield new targets for examination in these developmental diseases.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
7P01HD023315-26
Application #
8721258
Study Section
Special Emphasis Panel (ZHD1-MCHG-B (DC))
Program Officer
Grave, Gilman D
Project Start
1997-03-01
Project End
2014-06-30
Budget Start
2013-07-03
Budget End
2014-06-30
Support Year
26
Fiscal Year
2013
Total Cost
$1,376,743
Indirect Cost
$205,776
Name
Rbhs-Robert Wood Johnson Medical School
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
078795875
City
Piscataway
State
NJ
Country
United States
Zip Code
08854
Lee, Hee Jae; Dreyfus, Cheryl; DiCicco-Bloom, Emanuel (2016) Valproic acid stimulates proliferation of glial precursors during cortical gliogenesis in developing rat. Dev Neurobiol 76:780-98
Mony, Tamanna Jahan; Lee, Jae Won; Dreyfus, Cheryl et al. (2016) Valproic Acid Exposure during Early Postnatal Gliogenesis Leads to Autistic-like Behaviors in Rats. Clin Psychopharmacol Neurosci 14:338-344
Huang, Yangyang; Dreyfus, Cheryl F (2016) The role of growth factors as a therapeutic approach to demyelinating disease. Exp Neurol 283:531-40
Das, Gitanjali; Yu, Qili; Hui, Ryan et al. (2016) EphA5 and EphA6: regulation of neuronal and spine morphology. Cell Biosci 6:48
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
Sheleg, Michal; Yochum, Carrie L; Richardson, Jason R et al. (2015) Ephrin-A5 regulates inter-male aggression in mice. Behav Brain Res 286:300-7
Ma, Qian; Yang, Jianmin; Li, Thomas et al. (2015) Selective reduction of striatal mature BDNF without induction of proBDNF in the zQ175 mouse model of Huntington's disease. Neurobiol Dis 82:466-77
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
Yang, Jianmin; Harte-Hargrove, Lauren C; Siao, Chia-Jen et al. (2014) proBDNF negatively regulates neuronal remodeling, synaptic transmission, and synaptic plasticity in hippocampus. Cell Rep 7:796-806

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