Abstract

The overall goal of these studies is to define the role of Schwann cell gap junctions in the development and regeneration of peripheral nerve. The primary hypothesis is that mature myelinating Schwann cells express Cx32 in the form of reflexive contacts between paranodal and Schmidt-Lantermann incisures of a single cell, whereas proliferating Schwann cells in early development and distal to the site of nerve injury express another gap junction protein (CxS) that participates in intercellular coupling. Because point mutations in Cx32 are responsible for the X-linked form of Charcot-Marie-Tooth syndrome (CMTX), a demyelinating peripheral neuropathy, we will correlate changes in Cx32 expression with myelination in vivo and in culture. Because CxS expression and the proliferating phenotype are induced by nerve injury, we will examine the time course of changes after injury and effects on cultured cells of cytokines/growth factors to which Schwann cells are exposed after injury and during regeneration. We will apply a broadly based approach to these studies, taking advantage of recently developed animal models deficient in Cx32 and myelin proteins.
Specific Aim 1. Identify the connexins present in rodent nerve and determine developmental changes in expression and distribution of connexins and correlate with changes in major myelin proteins.
Specific Aim 2. Test the hypothesis that changes in connexin expression occur in peripheral nerve in response to various types of injury and in murine models of demyelinating disease.
Specific Aim 3. Test the hypothesis that mitogens released during or following nerve injury induce changes in connexin expression and function in cultured Schwann cells.
Specific Aim 4. Test the hypothesis that expression of gap junctions between Schwann cells during myelination in vivo will mimic developmental and regeneration changes in vivo. Together, the studies proposed in this application should greatly extend our knowledge of the cell biology of the Schwann cell and its modulation in pathological conditions.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS034931-03
Application #
2655526
Study Section
Special Emphasis Panel (ZRG2-PHY (04))
Program Officer
Nichols, Paul L
Project Start
1996-02-05
Project End
1999-01-31
Budget Start
1998-02-01
Budget End
1999-01-31
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
Albert Einstein College of Medicine
Department
Neurosciences
Type
Schools of Medicine
DUNS #
009095365
City
Bronx
State
NY
Country
United States
Zip Code
10461

  Publications

Bai, Donglin; del Corsso, Cristiane; Srinivas, Miduturu et al. (2006) Block of specific gap junction channel subtypes by 2-aminoethoxydiphenyl borate (2-APB). J Pharmacol Exp Ther 319:1452-8
Thi, Mia M; Kojima, Takashi; Cowin, Stephen C et al. (2003) Fluid shear stress remodels expression and function of junctional proteins in cultured bone cells. Am J Physiol Cell Physiol 284:C389-403
Duffy, Heather S; O'Donnell, Phyllis; Coombs, Wanda et al. (2003) Kinetics of protein-protein interactions of connexins: use of enzyme linked sorbent assays. Cell Commun Adhes 10:207-10
Iacobas, D A; Urban, Marcia; Iacobas, Sanda et al. (2002) Transcriptomic characterization of four classes of cell-cell/cell-matrix genes in brains and hearts of wild type and connexin43 null mice. Rom J Physiol 39-40:91-116
Iacobas, D A; Urban, Marcia; Iacobas, Sanda et al. (2002) Control and variability of gene expression in mouse brain and in a neuroblastoma cell line. Rom J Physiol 39-40:71-90
Zoidl, G; Meier, C; Petrasch-Parwez, E et al. (2002) Evidence for a role of the N-terminal domain in subcellular localization of the neuronal connexin36 (Cx36). J Neurosci Res 69:448-65
Rozental, R; Andrade-Rozental, A F; Zheng, X et al. (2001) Gap junction-mediated bidirectional signaling between human fetal hippocampal neurons and astrocytes. Dev Neurosci 23:420-31
De Pina-Benabou, M H; Srinivas, M; Spray, D C et al. (2001) Calmodulin kinase pathway mediates the K+-induced increase in Gap junctional communication between mouse spinal cord astrocytes. J Neurosci 21:6635-43
Duffy, H S; Delmar, M; Coombs, W et al. (2001) Functional demonstration of connexin-protein binding using surface plasmon resonance. Cell Commun Adhes 8:225-9
Srinivas, M; Hopperstad, M G; Spray, D C (2001) Quinine blocks specific gap junction channel subtypes. Proc Natl Acad Sci U S A 98:10942-7

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