The overall aim of our research is to understand how the growth of neurons is modulated by interaction with extracellular matrix molecules. This proposal centers upon understanding how the extracellular matrix molecule tenascin-C regulates neuronal growth. Tenascin-C is not a single molecule, but is instead a family of alternatively spliced variants containing different combinations of fibronectin type III domains. We have found that the region of tenascin-C containing only the alternately spliced fibronectin type III domains, called fnA-D, when used by itself, dramatically increases neurite outgrowth in culture. In fact, this molecule is the most potent growth promoter we have identified in our tests in culture. The alternatively spliced region also provides directional cues to growing neurites, which we define as neurite guidance. Neurites demonstrate a strong preference for fbA-D when they are given a choice at an interface. FnA-D even influences extension into normally repulsive chondroitin sulfate proteoglycans, the major inhibitory molecules in the glial scar. We have associated these features with different domains of the fnA-D molecule: promotion of neurite outgrowth with fnD (the seventh fibronectin type III domain), and neurite guidance with fnC (the sixth domain). More specifically we further localized the outgrowth activity to the 8 amino acids 29-36 within fnD which we call the """"""""outgrowth promoting motif"""""""" (OPM). We have also determined that an antibody directed against the OPM can reduce neurite outgrowth by tenascin-C, thus demonstrating that this region is functional within the intact molecule. Our initial goal is thus to explore the hypothesis that neurite outgrowth and neurite guidance mediated by fnA-D are distinct processes, each of which can be manipulated independently to encourage directed neuronal regrowth. In addition, we will explore the hypothesis that these domains of tenascin-C may have properties as soluble chemoattractant molecules.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS040394-02
Application #
6540302
Study Section
Special Emphasis Panel (ZRG1-MDCN-7 (01))
Program Officer
Kleitman, Naomi
Project Start
2001-06-01
Project End
2006-03-31
Budget Start
2002-04-01
Budget End
2003-03-31
Support Year
2
Fiscal Year
2002
Total Cost
$314,000
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Pharmacology
Type
Schools of Medicine
DUNS #
622146454
City
Piscataway
State
NJ
Country
United States
Zip Code
08854
Chen, Jian; Joon Lee, Hyun; Jakovcevski, Igor et al. (2010) The extracellular matrix glycoprotein tenascin-C is beneficial for spinal cord regeneration. Mol Ther 18:1769-77
Nur-E-Kamal, Alam; Ahmed, Ijaz; Kamal, Jabeen et al. (2008) Covalently attached FGF-2 to three-dimensional polyamide nanofibrillar surfaces demonstrates enhanced biological stability and activity. Mol Cell Biochem 309:157-66
Ahmed, Ijaz; Ponery, Abdul S; Nur-E-Kamal, Alam et al. (2007) Morphology, cytoskeletal organization, and myosin dynamics of mouse embryonic fibroblasts cultured on nanofibrillar surfaces. Mol Cell Biochem 301:241-9
Nur-E-Kamal, Alam; Meiners, Sally; Ahmed, Ijaz et al. (2007) Role of DNA topoisomerase IIbeta in neurite outgrowth. Brain Res 1154:50-60
Schindler, Melvin; Nur-E-Kamal, Alam; Ahmed, Ijaz et al. (2006) Living in three dimensions: 3D nanostructured environments for cell culture and regenerative medicine. Cell Biochem Biophys 45:215-27
Nur-E-Kamal, Alam; Ahmed, Ijaz; Kamal, Jabeen et al. (2006) Three-dimensional nanofibrillar surfaces promote self-renewal in mouse embryonic stem cells. Stem Cells 24:426-33
Ahmed, Ijaz; Liu, Hsing-Yin; Mamiya, Ping C et al. (2006) Three-dimensional nanofibrillar surfaces covalently modified with tenascin-C-derived peptides enhance neuronal growth in vitro. J Biomed Mater Res A 76:851-60
Nur-E-Kamal, Alam; Zhang, Ailing; Keenan, Susan M et al. (2005) Requirement of activated Cdc42-associated kinase for survival of v-Ras-transformed mammalian cells. Mol Cancer Res 3:297-305
Nur-E-Kamal, Alam; Ahmed, Ijaz; Kamal, Jabeen et al. (2005) Three dimensional nanofibrillar surfaces induce activation of Rac. Biochem Biophys Res Commun 331:428-34
Schindler, Melvin; Ahmed, Ijaz; Kamal, Jabeen et al. (2005) A synthetic nanofibrillar matrix promotes in vivo-like organization and morphogenesis for cells in culture. Biomaterials 26:5624-31

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