Damage to myelin from diseases such as multiple sclerosis (MS) results in the disruption of the nerve signal, damage to the axon, and finally degeneration. To date, there are no therapies for repair or remyelination in MS and this fact alone illustrates the greatest hope and unmet need for MS patients. Functional screening for small molecules or biologicals that promote remyelination represents a major hurdle to the identification and development of rational therapeutics for MS. Recently we implemented a novel functional screen using fabricated micropillar arrays to identify anti-muscarinic compounds that greatly enhance oligodendrocyte remyelination (Mei et al., 2014). As many of the promising compounds identified in our initial screen activated or antagonized G-protein coupled receptor (GPCR) targets, in this proposal, we focus screening efforts on GPCR small molecule libraries to identify/confirm/validate receptor targets that either inhibit or promote myelination. We believe that GPCRs represent targetable receptors and pathways for the development of small molecule therapeutics for MS. In this proposal we will: 1. Perform high-throughput screening of GPCR small molecule libraries to identify agonists and antagonists that promote myelination. 2. Identify, confirm and validate novel receptors and pathways responsible for the regulation of oligodendrocyte differentiation and myelination. 3. Investigate the therapeutic implications of activating or blocking specific receptors during development and after demyelination. Overall, we believe that our proposal will not only impart a valuable technical approach but more importantly our data identifies two specific GPCRs, the muscarinic receptor 1 (M1R) that inhibits (Gq) and the kappa opioid receptor (KOR) that promotes (Gi/Go) differentiation and myelination of oligodendrocytes both during development and after demyelination.

Public Health Relevance

Damage to myelin from diseases such as multiple sclerosis (MS) results in the disruption of the nerve signal, damage to the axon, and finally degeneration. Functional screening for small molecules or biologicals that promote remyelination represents a major hurdle to the identification and development of rational therapeutics for MS. Our proposal will not only impart a valuable technical advance but more importantly will provide insight into two receptor targets that modulate the development of oligodendrocytes and repair after demyelination.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS095889-04
Application #
9731682
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Utz, Ursula
Project Start
2016-09-01
Project End
2021-06-30
Budget Start
2019-07-01
Budget End
2020-06-30
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Neurology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94118
Domingues, Helena S; Cruz, Andrea; Chan, Jonah R et al. (2018) Mechanical plasticity during oligodendrocyte differentiation and myelination. Glia 66:5-14
Wang, Fei; Yang, Yu-Jian; Yang, Nian et al. (2018) Enhancing Oligodendrocyte Myelination Rescues Synaptic Loss and Improves Functional Recovery after Chronic Hypoxia. Neuron 99:689-701.e5
Pease-Raissi, Sarah E; Chan, Jonah R (2018) Micro(glial)-managing executive function: white matter inflammation drives catatonia. J Clin Invest 128:564-566
Mayoral, Sonia R; Etxeberria, Ainhoa; Shen, Yun-An A et al. (2018) Initiation of CNS Myelination in the Optic Nerve Is Dependent on Axon Caliber. Cell Rep 25:544-550.e3
Dombrowski, Yvonne; O'Hagan, Thomas; Dittmer, Marie et al. (2017) Regulatory T cells promote myelin regeneration in the central nervous system. Nat Neurosci 20:674-680
Petersen, Mark A; Ryu, Jae Kyu; Chang, Kae-Jiun et al. (2017) Fibrinogen Activates BMP Signaling in Oligodendrocyte Progenitor Cells and Inhibits Remyelination after Vascular Damage. Neuron 96:1003-1012.e7
Pan, Simon; Chan, Jonah R (2017) Regulation and dysregulation of axon infrastructure by myelinating glia. J Cell Biol 216:3903-3916
Osso, Lindsay A; Chan, Jonah R (2017) Architecting the myelin landscape. Curr Opin Neurobiol 47:1-7
Wu, Lai Man Natalie; Wang, Jincheng; Conidi, Andrea et al. (2016) Zeb2 recruits HDAC-NuRD to inhibit Notch and controls Schwann cell differentiation and remyelination. Nat Neurosci 19:1060-72
Mei, Feng; Mayoral, Sonia R; Nobuta, Hiroko et al. (2016) Identification of the Kappa-Opioid Receptor as a Therapeutic Target for Oligodendrocyte Remyelination. J Neurosci 36:7925-35

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