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. Brain damage in multiple sclerosis (MS) is marked by a destruction of the insulating sheath, known as myelin, wrapped around nerves. Although substantial efforts have centered on suppression of the immune response that attacks myelin, it is becoming clear that it does not address the major problem of the disease: loss of myelin. CNS myelin is produced by specialized cells called oligodendrocytes. A common feature of demyelinated lesions is the differentiation block of oligodendrocyte precursors (OPC) at a pre-myelinating stage. Thus, the identification of the critical factors that promote oligodendrocyt production from OPCs and block the inhibitory signals for myelination will help to improve myelin repair and devise effective treatment strategies for demyelinating diseases. Ultimately the myelination program is controlled at the level of gene regulation. Histone deacetylases play an important role in the regulation of gene expression by modifying both histones and non-histone regulatory proteins, thereby controlling how cells grow and differentiate. Recently we demonstrated that class I histone deacetylases, HDAC1/2, are essential for OPC proliferation and differentiation. Our preliminary data indicate that deletion of another class I histone deacetylase, Hdac3, in the oligodendrocyte lineage resulted in severe myelination deficits. Our central hypothesis is that Hdac3 and its mediators are required for establishing oligodendrocyte identity and controlling the myelination process in the CNS. The objective of this application is to gain a crucial insight into the molecular basis of the myelination process regulated by Hdac3 and its co-factor complex. We will utilize in vivo mutagenesis approaches to define the role of Hdac3 in CNS myelination and myelin repair by analyzing new conditional knockout mouse strains, NG2-CreERT:Hdac3 flox/flox and Plp-CreERT:Hdac3 flox/flox mice, in which Hdac3 is selectively ablated in OPC and differentiating OL, respectively, in a developmentally-controlled manner. In addition, we will identify and characterize the direct targets of Hdac3 that control the myelination program by employing genome-wide RNA-sequencing (RNA-seq) and chromatin-immunoprecipitation-sequencing (ChIP-seq) strategies. The long-term goal of the research proposed here is to foster the development of agents that modulate the activity of Hdac3 and its downstream effectors to promote myelination and, of urgent clinical relevance, remyelination. The proposed studies will not only advance our understanding of the mechanisms of CNS myelination, but also identify potential therapeutic targets to promote oligodendrocyte regeneration and myelin repair for the patients with demyelinating diseases such as MS, leukodystrophies, stroke, and injury to the brain or spinal cord.

Public Health Relevance

Demyelination in the central nervous system (CNS) could lead to various neurological diseases by impairing nerve conduction, cognitive and motor function. The proposed research will provide a better understanding of molecular control of CNS myelination and remyelination. It is relevant to the part of NIH's mission because the proposed studies will not only have scientific merits but also could offer new strategies in treating patiens with demyelinating diseases such as multiple sclerosis, cerebral palsy and spinal cord injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS072427-09
Application #
9353880
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Morris, Jill A
Project Start
2010-09-15
Project End
2020-08-31
Budget Start
2017-09-01
Budget End
2018-08-31
Support Year
9
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
Zheng, Zhen; Zhang, Li; Qu, Yi et al. (2018) Mesenchymal Stem Cells Protect Against Hypoxia-Ischemia Brain Damage by Enhancing Autophagy Through Brain Derived Neurotrophic Factor/Mammalin Target of Rapamycin Signaling Pathway. Stem Cells :
Zhao, Chuntao; Dong, Chen; Frah, Magali et al. (2018) Dual Requirement of CHD8 for Chromatin Landscape Establishment and Histone Methyltransferase Recruitment to Promote CNS Myelination and Repair. Dev Cell 45:753-768.e8
Weng, Qinjie; Wang, Jiaying; Wang, Jiajia et al. (2018) Lenalidomide regulates CNS autoimmunity by promoting M2 macrophages polarization. Cell Death Dis 9:251
Lu, Xu-Feng; Cao, Xiao-Yue; Zhu, Yong-Jie et al. (2018) Histone deacetylase 3 promotes liver regeneration and liver cancer cells proliferation through signal transducer and activator of transcription 3 signaling pathway. Cell Death Dis 9:398
He, Xuelian; Zhang, Liguo; Queme, Luis F et al. (2018) A histone deacetylase 3-dependent pathway delimits peripheral myelin growth and functional regeneration. Nat Med 24:338-351
Zuo, Hao; Wood, William M; Sherafat, Amin et al. (2018) Age-Dependent Decline in Fate Switch from NG2 Cells to Astrocytes After Olig2 Deletion. J Neurosci 38:2359-2371
Jiang, Minqing; Rao, Rohit; Wang, Jincheng et al. (2018) The TSC1-mTOR-PLK axis regulates the homeostatic switch from Schwann cell proliferation to myelination in a stage-specific manner. Glia 66:1947-1959
Wu, Lai Man Natalie; Deng, Yaqi; Wang, Jincheng et al. (2018) Programming of Schwann Cells by Lats1/2-TAZ/YAP Signaling Drives Malignant Peripheral Nerve Sheath Tumorigenesis. Cancer Cell 33:292-308.e7
Merten, Nicole; Fischer, Julia; Simon, Katharina et al. (2018) Repurposing HAMI3379 to Block GPR17 and Promote Rodent and Human Oligodendrocyte Differentiation. Cell Chem Biol 25:775-786.e5
Gregath, Alexander; Lu, Qing Richard (2018) Epigenetic modifications-insight into oligodendrocyte lineage progression, regeneration, and disease. FEBS Lett 592:1063-1078

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