The long-term goal of this research proposal is to understand the developmental mechanisms of CNS progenitor differentiation. More specifically the focus of this grant is to elucidate the mechanisms responsible for the transition from the late progenitor stage to terminal differentiation. Using the oligodendrocyte (OL) lineage as model system, this experimental plan tests the hypothesis that histone deacetylation is a crucial event during this transition. The model being tested is that """"""""activation"""""""" of the OL differentiation program occurs through a de-repression mechanism, mediated by histone deacetylation. This model implies that progenitors are maintained in an undifferentiated state by """"""""inhibitory"""""""" mechanisms that prevent the cytoskeletal changes and the pattern of gene expression characteristic of the mature phenotype. The transition to terminal differentiation is characterized by disinhibition of these mechanisms due to histone deacetylation.
Specific Aim 1 tests the hypothesis that histone deacetylation is essential for decreasing the expression of microtubule (i.e. stathmin) and microfilament (i.e. gelsolin) severing proteins which are important for the morphological changes characteristic of terminally differentiated oligodendrocytes.
Specific Aim 2 tests the hypothesis that histone deacetylation contributes to the myelin gene activation DIRECTLY, by compacting chromatin in the negative regulatory regions of their promoters.
Specific Aim 3 tests the hypothesis that histone deacetylation contributes to activation of myelin gene expression INDIRECTLY, by regulating chromatin compaction in the promoter region of genes encoding inhibitory molecules. The results of these studies are expected to have broad implications for the current concept of developmental regulation of gene expression and also for remyelination therapies in multiple sclerosis and after CNS injury. Furthermore, by addressing the regulation of genes whose expression is altered in glial tumors, they may contribute to the general knowledge of neoplastic transformation of glial progenitor.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS042925-03S1
Application #
7085157
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Utz, Ursula
Project Start
2003-03-01
Project End
2007-02-28
Budget Start
2005-03-01
Budget End
2006-02-28
Support Year
3
Fiscal Year
2005
Total Cost
$6,998
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Neurosciences
Type
Schools of Medicine
DUNS #
617022384
City
Piscataway
State
NJ
Country
United States
Zip Code
08854
Ntranos, Achilles; Casaccia, Patrizia (2018) The Microbiome-Gut-Behavior Axis: Crosstalk Between the Gut Microbiome and Oligodendrocytes Modulates Behavioral Responses. Neurotherapeutics 15:31-35
Castro, Kamilah; Casaccia, Patrizia (2018) Epigenetic modifications in brain and immune cells of multiple sclerosis patients. Mult Scler 24:69-74
Moyon, Sarah; Liang, Jialiang; Casaccia, Patrizia (2016) Epigenetics in NG2 glia cells. Brain Res 1638:183-198
Hernandez, Marylens; Casaccia, Patrizia (2015) Interplay between transcriptional control and chromatin regulation in the oligodendrocyte lineage. Glia 63:1357-75
Huynh, Jimmy L; Garg, Paras; Thin, Tin Htwe et al. (2014) Epigenome-wide differences in pathology-free regions of multiple sclerosis-affected brains. Nat Neurosci 17:121-30
Gacias, Mar; Gerona-Navarro, Guillermo; Plotnikov, Alexander N et al. (2014) Selective chemical modulation of gene transcription favors oligodendrocyte lineage progression. Chem Biol 21:841-854
Vidaurre, Oscar G; Liu, Jia; Haines, Jeffery et al. (2012) An integrated approach to design novel therapeutic interventions for demyelinating disorders. Eur J Neurosci 35:1879-86
Wu, Muzhou; Hernandez, Marylens; Shen, Siming et al. (2012) Differential modulation of the oligodendrocyte transcriptome by sonic hedgehog and bone morphogenetic protein 4 via opposing effects on histone acetylation. J Neurosci 32:6651-64
Casaccia, Patrizia (2011) Anti-TANKyrase weapons promote myelination. Nat Neurosci 14:945-7
Pedre, Xiomara; Mastronardi, Fabrizio; Bruck, Wolfgang et al. (2011) Changed histone acetylation patterns in normal-appearing white matter and early multiple sclerosis lesions. J Neurosci 31:3435-45

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