Demyelinating diseases of the central nervous system (CNS) such as multiple sclerosis (MS) are among the most devastating and disabling disorders, leading to severe handicap and even death. A common feature of demyelinated lesions is the differentiation block of oligodendrocyte precursors (OPC) at a premyelinating stage. However, at present, the mechanistic basis for failure of proper myelin repair is not fully understood. Understanding the molecular control of myelination and remyelination is crucial for treating demyelinating diseases. A large body of work has shown that chromatin-remodeling events govern the transcriptional and epigenetic establishment of the cellular differentiation program. Chromatin remodeling enzymes including histone modifying enzymes and ATP-dependent chromatin remodelers modulate local chromatin structure and facilitate recruitment of essential factors required for gene expression. Recently we demonstrated the histone deacetylases HDAC1/2 are essential for oligodendrocyte myelination. In a search of HDAC1/2-interacting proteins, we identified Brg1 (Brahma-related gene-1), the central catalytic subunit of SWI/SNF-like chromatin-modifying enzymatic complex, which was found associated with HDAC1/2 in oligodendrocytes. Deletion of Brg1 in the oligodendrocyte lineage resulted in severe myelination deficits, suggesting that Brg1 is critical for the control of CNS myelination. I addition, in a search of Brg1 downstream genes we identified an oligodendrocyte-enriched ATP dependent chromatin-remodeler Chd7, mutations of which causes CHARGE syndrome with severe neurological disorders. The goal of this proposal is to gain a better insight into the molecular basis of the myelination process regulated by Brg1 and its downstream genes. We will utilize conditional in vivo mutagenesis approaches to define the role of Brg1 in CNS myelination and myelin repair in a spatiotemporally controlled manner. In addition, a genome-wide target gene screen will be used to identify Brg1-regulated genes that control myelination. The long-term objective of the research proposed here is to develop compounds that modulate the activity of Brg1 complexes and its downstream effectors to promote myelination and remyelination. The proposed studies will not only advance our understanding of the mechanisms of CNS myelination, but also identify potential targets for treating patients with demyelinating diseases such as MS, leukodystrophies, stroke, spinal cord and brain injury.
The studies proposed in research plans will provide a better understanding of molecular control of CNS myelination and remyelination. They will not only have scientific merits but also could offer new strategies in treating patients with demyelinating neurological disorders such as multiple sclerosis; periventricular cerebral palsy; the common cause of severe disability in infants; stroke and spinal cord injury.
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