Therapeutic Targeting of Intracellular Mechanisms Involved in Glial Scar Formatio

Summary

Principal Investigator: Damien D Pearse
Abstract: DESCRIPTION (provided by applicant): Glial scarring following CNS injury alters the lesion environment so as to impede axonal regeneration and plasticity, thereby limiting functional restitution. Reactive astrocytes are the main cellular component of the glial scar;astrocytes undergo morphological changes and produce extracellular matrix, such as chondroitin sulfate proteoglycans (CSPGs), which physically and chemically inhibit axon growth. Strategies that inhibit astrogliosis or prevent the synthesis of, or degrade, CSPGs have been demonstrated to relieve axon growth inhibition and improve function. Intracellular mechanisms involved in the control of astrocyte reactivity and the stimulation of CSPG production remain poorly understood. Recent reports have shown that the phosphodiesterase (PDE) inhibitor Rolipram can reduce astrogliosis and Preliminary Data from our laboratory indicates that there is a chronic induction of the PDE4A isozyme in reactive astrocytes that occurs in parallel with the maturation of the glial scar. Site-specific targeting of this PDE4 isoform may then prevent astrogliosis and offer a novel therapeutic direction for scar reduction after injury to the spinal cord or brain so as to enhance axon plasticity and functional recovery. To delineate the role of PDE4A in astrocyte reactivity and CSPG production, interference RNA will be used via lentiviral vector expressed PDE4A short-hairpin RNA (shRNA) specifically within astrocytes in vitro [Specific Aim 1] and in vivo (gfap-promoter driven) after spinal cord injury (SCI) [Specific Aim 2]. In astrocyte cultures, the effectiveness of PDE4A knockdown will be refined and the role of PDE4A in mechanisms of cellular reactivity, including A) cytoskeletal rearrangements, B) enhanced cell migration, C) increased cell proliferation and, D) the production of CSPGs, will be examined. Then in vivo, these in vitro effects will be corroborated as well as the anatomical and functional benefits of PDE4A knockdown in repair assessed. A complete transection SCI model will be used to assess if PDE4A knockdown in astrocytes prevents axon dieback and/or allows axonal regeneration across the injury site, while the functional effects of molecular PDE4A inhibition in astrocytes will be examined in an incomplete contusive SCI paradigm.
Funding Period: 2012-06-01 - 2014-05-31
more information: NIH RePORT

Detail Information

Research Grants30

  1. HDAC6: a target for regeneration following injury in the nervous system
    BRETT CAMERON LANGLEY; Fiscal Year: 2013
    ..Our findings in this project could lead to new treatments for spinal cord injury and other central nervous system injuries and disease. ..
  2. Plasticity and Repair in the Phrenic Motor System
    Paul J Reier; Fiscal Year: 2013
    ..gray matter contributions to other SCI-related functional outcomes. ..
  3. The Effects of GDNF on Peripheral Nerve Regeneration
    Shelly Elese Sakiyama-Elbert; Fiscal Year: 2013
    ..2) To determine the effect of increased GDNF levels on SCs and define their role in GDNF enhanced regeneration after peripheral nerve injury. ..
  4. Expanding the National Health Accounts
    David M Cutler; Fiscal Year: 2013
    ..Establishment of a set of national health accounts will allow us as a society to understand which medical interventions improve the health of the U.S. population most efficiently. ..
  5. Controlled Release Scaffolds for Nerve Regeneration
    Lonnie D Shea; Fiscal Year: 2013
    ..Controllable systems such as this will identify the contribution of each component to functional outcome, and can be tuned to obtain the functionality necessary for translation to the clinic. ..
  6. INITIATION OF HUMAN LABOR: PREVENTION OF PREMATURITY
    Carole R Mendelson; Fiscal Year: 2013
    ..We propose that these interrelated projects, carried out by a highly interactive research team, will achieve the long-range goals of this Program and contribute to a reduction in the incidence of preterm birth. ..
  7. Transplantation of Neural Progenitors as Functional Relay for Spinal Cord Injury
    PENGZHE LU; Fiscal Year: 2013
    ..Further, this model system will provide a rich opportunity for identifying molecular mechanisms underlying axonal regeneration. The goals of this research are directly and highly relevant to the VA patient care mission. ..
  8. Recovery of bladder reflexes and nerve regeneration after spinal cord injury
    Yu Shang Lee; Fiscal Year: 2013
    ..This multipartite strategy has the potential to lead to an unprecedented amount of functional plasticity/regeneration and bladder recovery after SCI. ..
  9. Indiana University Center for Pediatric Pharmacology
    Jamie L Renbarger; Fiscal Year: 2013
    ..The direct outcome of these studies will be new biomarkers and predictive signatures that will increase the precision of the existing dosing schemas used in the treatment of childhood cancer. ..
  10. Axons and the extracellular matrix in spinal cord injury
    Dana M McTigue; Fiscal Year: 2013
    ..These results will provide essential information about the function of cells surrounding the lesion site and serve as an important part of future combination strategies to reduce tissue loss and support axonal growth after SCI. ..
  11. GENE THERAPY FOR METABOLIC DISORDERS
    Chester B Whitley; Fiscal Year: 2013
    ..abstract_text> ..
  12. Spinal Cord Injury, Plasticity and Transplant Mediated Repair
    John D Houle; Fiscal Year: 2013
    ..This Program Project has direct relevance to the design and implementation of future treatment programs for acute and delayed intervention after SCI. ..
  13. Dynamics of axon regeneration with in vivo imaging and conventional injury models
    Ariana Lorenzana; Fiscal Year: 2013
    ..This intensive research plan is accompanied by a comprehensive training plan so that the applicant will acquire the skills necessary in order to develop into an independent researcher in future. ..