The long-term goal of this research is to understand the role of Scn1b, encoding voltage-gated Na+ channel ?1, in CNS myelinating glia. The objective is first, to measure ?1 expression in wildtype myelin and to characterize myelinating glia-specific Scn1b null mice. This powerful model provides a unique opportunity to study the role of Scn1b in myelination and axo-glial communication. Second, the objective is to determine the signal transduction mechanisms initiated by ?1-mediated cell-cell adhesion in oligodendrocyte precursor cells (OPCs) or oligodendrocytes (OLs). The overall goal of this proposal is to test the central hypothesis that ?1 is expressed in OPCs/OLs, in addition to axons, where it contributes to axo-glial communication through cell adhesion and modulation of electrical activity.
Two specific aims are proposed:
Aim 1. To determine the role of glial-expressed Scn1b in myelination. Preliminary Data demonstrate that mice that lack Scn1b in myelinating glia have movement disorders, dysmyelination, delayed myelination or lack of myelination, and axonal degeneration. These data support the working hypothesis of this aim that Scn1b plays a critical role in OPC development and/or axo-glial communication.
Aim 2. To determine the role of Scn1b in OPC/OL signal transduction. The working hypothesis here is that ?1-?1 interactions play a key role in recognition of axons by glia and subsequent initiation of myelination via a signaling cascade in glia that involves the CAM contactin as well as fyn kinase activation. Further, it is proposed that ?1 modulation of Na+ currents plays a role in OPC development, including proliferation, migration, and spacing along axons, and thus may contribute to the initiation of myelination. With respect to expected outcomes, the work proposed in Aims 1 and 2 is expected define a novel role for ?1 in OPC signaling, including axo-glial communication. These results are expected to have an important positive impact on the fields of demyelinating and hypomyelinating disease. Rapid processing of information in the CNS requires efficient saltatory conduction of action potentials along myelinated axons. Disruptions in myelination result in a range of human neurological diseases, including multiple sclerosis in adults and leukodystrophies in children. While human mutations in SCN1B associated with demyelination, dysmyelination, or hypomyelination have not yet been identified, they have been determined to play a role in other neurological diseases, including severe epilepsy associated with mental retardation. A detailed understanding of the basic mechanisms underlying the role of SCN1B in axo-glial communication is essential to the future development of novel therapeutic regimens for demyelinating disease.
Disruptions in myelination and axo-glial communication result in a range of human neurological diseases, including Multiple Sclerosis. While mutations in Scn1b associated with central demyelination or dysmyelination have not yet been identified, a detailed understanding of the basic mechanisms underlying communication between the axon and the myelin sheath is essential to the future development of novel therapeutic regimens for Multiple Sclerosis. In the present application, it is proposed to investigate the role of Scn1b in CNS myelin formation, ultrastructure of the myelin sheath, and axonal degeneration, with the future goal of developing novel therapies to promote remyelination and axon protection in pathophysiology.
| Bao, Yangyang; Willis, B Cicero; Frasier, Chad R et al. (2016) Scn2b Deletion in Mice Results in Ventricular and Atrial Arrhythmias. Circ Arrhythm Electrophysiol 9: |
| O'Malley, Heather A; Isom, Lori L (2015) Sodium channel ? subunits: emerging targets in channelopathies. Annu Rev Physiol 77:481-504 |
| Lee, Amy; Fakler, Bernd; Kaczmarek, Leonard K et al. (2014) More than a pore: ion channel signaling complexes. J Neurosci 34:15159-69 |
| Liu, Yu; Lopez-Santiago, Luis F; Yuan, Yukun et al. (2013) Dravet syndrome patient-derived neurons suggest a novel epilepsy mechanism. Ann Neurol 74:128-39 |
| Yang, Ming; Kozminski, David J; Wold, Lindsey A et al. (2012) Therapeutic potential for phenytoin: targeting Na(v)1.5 sodium channels to reduce migration and invasion in metastatic breast cancer. Breast Cancer Res Treat 134:603-15 |
| Chen, Chunling; Calhoun, Jeffrey D; Zhang, Yanqing et al. (2012) Identification of the cysteine residue responsible for disulfide linkage of Na+ channel ? and ?2 subunits. J Biol Chem 287:39061-9 |
| Patino, Gustavo A; Brackenbury, William J; Bao, Yangyang et al. (2011) Voltage-gated Na+ channel ?1B: a secreted cell adhesion molecule involved in human epilepsy. J Neurosci 31:14577-91 |
| Lin, Xianming; Liu, Nian; Lu, Jia et al. (2011) Subcellular heterogeneity of sodium current properties in adult cardiac ventricular myocytes. Heart Rhythm 8:1923-30 |
| Brackenbury, William J; Isom, Lori L (2011) Na Channel ? Subunits: Overachievers of the Ion Channel Family. Front Pharmacol 2:53 |
| O'Malley, Heather A; Park, Yanghae; Isom, Lori L et al. (2010) PKCbeta co-localizes with the dopamine transporter in mesencephalic neurons. Neurosci Lett : |
Showing the most recent 10 out of 11 publications
