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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
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Special Emphasis Panel (ZHD1-MCHG-B (DC))
Program Officer
Grave, Gilman D
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Rbhs-Robert Wood Johnson Medical School
Other Basic Sciences
Schools of Medicine
United States
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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
Huang, Yangyang; Dreyfus, Cheryl F (2016) The role of growth factors as a therapeutic approach to demyelinating disease. Exp Neurol 283:531-40
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
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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 82:466-477
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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
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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