MMPs in neural networking

Summary

Principal Investigator: KATHERINE E CONANT
Abstract: [unreadable] DESCRIPTION (provided by applicant): Evidence suggests that integrins may be critical to the establishment and maintenance of neuronal networks. Integrins are involved in the directed migration of both neurons and their processes, and a number of studies suggest they are also involved in the stabilization of synapses. The ability of integrins to play a role in neural networking is understandably influenced by the nature and availability of integrin binding ligands. These ligands include cell surface receptors, soluble molecules such as the semaphorins, and select proteins of the extracellular matrix (ECM). Recent studies have shown that both neural networking and the availability of integrin binding ligands may be altered in the setting of central nervous system (CNS) inflammation. For example, in simian immunodeficiency virus encephalitis (SIVE), synaptic damage and loss of perineuronal matrix has been demonstrated. Similarly, in human immunodeficiency dementia, a loss of dendritic arbor has been observed. And with respect to changes that may occur in development, in utero infection with cytomegalovirus has been linked to disrupted cortical organization. While multiple mechanisms are likely to contribute to disordered neural networking in the context of inflammation, matrix metalloproteinase (MMP) mediated changes in integrin function are likely to play an important role. MMPs degrade constituents of the ECM that are known to interact with integrins, and select MMPs have also been shown to directly associate with cell surface integrins. In the present proposal, we outline plans to test the hypothesis that MMPs will interfere with neuronal migration and with the formation or maintenance of synapses. We will also test the hypothesis that such effects are dependent on neuronal integrins. The results of our studies should improve our understanding of those CNS inflammatory diseases that are characterized by elevated levels of MMPs. [unreadable] [unreadable] [unreadable]
Funding Period: 2005-07-15 - 2007-06-30
more information: NIH RePORT

Top Publications

  1. ncbi The matrix metalloproteinases and CNS plasticity: an overview
    E A Milward
    School of Biomedical Sciences, University of Newcastle and Hunter Medical Research Institute, Callaghan NSW 2308, Australia
    J Neuroimmunol 187:9-19. 2007
  2. pmc Serum matrix metalloproteinase levels correlate with brain injury in human immunodeficiency virus infection
    Ann B Ragin
    Department of Radiology, Northwestern University, Chicago, Illinois 60611 2927, USA
    J Neurovirol 15:275-81. 2009
  3. pmc Marked relationship between matrix metalloproteinase 7 and brain atrophy in HIV infection
    Ann B Ragin
    Department of Radiology, Northwestern University, 737 N Michigan Avenue, Suite 1600, Chicago, IL 60611 2927, USA
    J Neurovirol 17:153-8. 2011
  4. pmc Cleavage of myelin associated glycoprotein by matrix metalloproteinases
    Elizabeth Milward
    School of Biomedical Sciences, The University of Newcastle and the Hunter Medical Research Institute, Callaghan, New South Wales 2308, Australia
    J Neuroimmunol 193:140-8. 2008
  5. pmc MMP-7 cleaves the NR1 NMDA receptor subunit and modifies NMDA receptor function
    Arek Szklarczyk
    Johns Hopkins University, Department of Neurology, Pathology Bldg Rm 625, 600 N Wolfe St, Baltimore, MD 21287, USA
    FASEB J 22:3757-67. 2008

Scientific Experts

  • Ann Ragin
  • Elizabeth A Milward
  • Arek Szklarczyk
  • Katherine Conant
  • Yue Wang
  • Richard Huganir
  • Osefame Ewaleifoh
  • Mark P Mattson
  • Tanya Malpica
  • Jean Claude Beique
  • David Knorr
  • Norman Haughey

Detail Information

Publications5

  1. ncbi The matrix metalloproteinases and CNS plasticity: an overview
    E A Milward
    School of Biomedical Sciences, University of Newcastle and Hunter Medical Research Institute, Callaghan NSW 2308, Australia
    J Neuroimmunol 187:9-19. 2007
    ....
  2. pmc Serum matrix metalloproteinase levels correlate with brain injury in human immunodeficiency virus infection
    Ann B Ragin
    Department of Radiology, Northwestern University, Chicago, Illinois 60611 2927, USA
    J Neurovirol 15:275-81. 2009
    ..MMPs may influence neurological outcome through involvement in neuroimmune response, blood-brain barrier permeability, leukocyte migration, and MMP-mediated neurotoxicity...
  3. pmc Marked relationship between matrix metalloproteinase 7 and brain atrophy in HIV infection
    Ann B Ragin
    Department of Radiology, Northwestern University, 737 N Michigan Avenue, Suite 1600, Chicago, IL 60611 2927, USA
    J Neurovirol 17:153-8. 2011
    ..MMP-7 was also correlated with measures of virologic and cognitive status...
  4. pmc Cleavage of myelin associated glycoprotein by matrix metalloproteinases
    Elizabeth Milward
    School of Biomedical Sciences, The University of Newcastle and the Hunter Medical Research Institute, Callaghan, New South Wales 2308, Australia
    J Neuroimmunol 193:140-8. 2008
    ..We conclude that MMPs may have the potential both to disrupt MAG dependent axon-glia communication and to generate bioactive fragments that can inhibit neurite growth...
  5. pmc MMP-7 cleaves the NR1 NMDA receptor subunit and modifies NMDA receptor function
    Arek Szklarczyk
    Johns Hopkins University, Department of Neurology, Pathology Bldg Rm 625, 600 N Wolfe St, Baltimore, MD 21287, USA
    FASEB J 22:3757-67. 2008
    ..In addition, the AMPA/NMDA ratio is increased by MMP-7 pretreatment. These data suggest that synaptic function may be altered in neurological conditions associated with increased levels of MMP-7...