Role of Protease Activated Receptors in Spinal Cord Injury and Repair

Summary

Principal Investigator: Isobel A Scarisbrick
Abstract: PROJECT SUMMARY/ABSTRACT Trauma to the spinal cord promotes a complex cascade of pathophysiological events that result in greater injury than was initially sustained and which contribute to inflammation, demyelination, axon injury and an unfavorable environment for neural recovery. The factors which drive this cascade continue to be identified and critically evaluated since each may serve as a target for the rationale design of new therapies to mitigate injury and to promote repair and regeneration. Work in our laboratory during the previous funding period indicates that serine proteases of the kallikrein (KLK) family are among the complex cascade of enzymes now recognized to be deregulated with spinal cord trauma and furthermore that several KLKs are novel mediators of neurotoxicity, astrogliosis and demyelination. Importantly, we discovered that KLKs exert their cellular effects by cleaving thereby activating G-protein coupled receptors termed Protease Activated Receptors (PARs). As cell surface receptors, PARs endow the cell with the ability to respond, or to over respond, to the rapidly changing proteolytic microenvironment that occurs at sites of CNS trauma, inflammation and blood brain barrier breakdown. The CENTRAL HYPOTHESIS to be tested in the proposed studies is that proteolytic activation of select PARs regulates unique cellular responses in the traumatically injured spinal cord and that these receptors can be differentially targeted to prevent secondary injury and to promote repair. If this hypothesis is correct, PARs may serve as targets for the development of new therapies. Four complementary Aims that focus on cellular, molecular and systems outcomes are proposed to test this hypothesis. In Aim 1, we will determine the effects of genetic targeting of PARs on neurobehavioral recovery in a murine model of traumatic spinal cord injury. In Aim 2, we will use genetic and pharmacologic loss and gain of function approaches to establish the role of PARs in mediating the cellular effects of SCI-related PAR agonists (KLKs, thrombin and plasmin) in primary spinal cord neurons, astrocytes and oligodendroglia and their sensitivity to neurotoxic agents in vitro. In Aim 3, we will dissect the molecular signaling and gene expression profiles that are elicited by each protease across neurons and neuroglia and the PARs responsible for mediating these effects. In Aim 4, we will determine the effects of PAR-pharmacotherapy on neurobehavioral recovery in murine traumatic SCI. The proposed studies will identify new receptor based mechanisms regulating the SCI microenvironment that are potentially highly amenable to therapeutic intervention and given the widespread expression of PARs in the CNS, are likely to be of fundamental significance to understanding injury and repair mechanisms in a wide range of neurological conditions.
Funding Period: 2005-07-01 - 2018-06-30
more information: NIH RePORT

Top Publications

  1. pmc The multiple sclerosis degradome: enzymatic cascades in development and progression of central nervous system inflammatory disease
    I A Scarisbrick
    Departmen of Physical Medicine, Mayo College of Medicine, 200 First St SW Rochester, MN 55905, USA
    Curr Top Microbiol Immunol 318:133-75. 2008
  2. pmc Critical role for PAR1 in kallikrein 6-mediated oligodendrogliopathy
    Joshua E Burda
    Neurobiology of Disease Program, Mayo Medical and Graduate School, Rochester, Minnesota, USA
    Glia 61:1456-70. 2013
  3. pmc Kallikrein 6 signals through PAR1 and PAR2 to promote neuron injury and exacerbate glutamate neurotoxicity
    Hyesook Yoon
    Neurobiology of Disease Program, Mayo Medical and Graduate School, Rochester, Minnesota, USA Department of Physical Medicine and Rehabilitation, Mayo Medical and Graduate School, Rochester, Minnesota, USA
    J Neurochem 127:283-98. 2013
  4. pmc Activation profiles of human kallikrein-related peptidases by matrix metalloproteinases
    Hyesook Yoon
    Department of Biomedical Sciences, Florida State University, Tallahassee, FL 32306 4300, USA
    Biol Chem 394:137-47. 2013
  5. pmc Kallikrein 6 is a novel molecular trigger of reactive astrogliosis
    Isobel A Scarisbrick
    Neurobiology of Disease Program, Mayo Medical and Graduate School, Rochester, MN 55905, USA
    Biol Chem 393:355-67. 2012
  6. pmc Kallikrein 6 regulates early CNS demyelination in a viral model of multiple sclerosis
    Isobel A Scarisbrick
    Neurobiology of Disease Program, Mayo Medical and Graduate School, Rochester, MN, USA
    Brain Pathol 22:709-22. 2012
  7. pmc Functional role of kallikrein 6 in regulating immune cell survival
    Isobel A Scarisbrick
    Neurobiology of Disease Program, Mayo Medical and Graduate School, Rochester, Minnesota, United States of America
    PLoS ONE 6:e18376. 2011
  8. pmc Functional intersection of the kallikrein-related peptidases (KLKs) and thrombostasis axis
    Michael Blaber
    Department of Biomedical Sciences, Florida State University, Tallahassee, 32306 4300, USA
    Biol Chem 391:311-20. 2010
  9. pmc A completed KLK activome profile: investigation of activation profiles of KLK9, 10, and 15
    Hyesook Yoon
    Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306 4300, USA
    Biol Chem 390:373-7. 2009
  10. pmc Protease-activated receptor dependent and independent signaling by kallikreins 1 and 6 in CNS neuron and astroglial cell lines
    Alexander G Vandell
    Molecular Neuroscience Program, Mayo Medical and Graduate School, Rochester, Minnesota 55905, USA
    J Neurochem 107:855-70. 2008

Detail Information

Publications13

  1. pmc The multiple sclerosis degradome: enzymatic cascades in development and progression of central nervous system inflammatory disease
    I A Scarisbrick
    Departmen of Physical Medicine, Mayo College of Medicine, 200 First St SW Rochester, MN 55905, USA
    Curr Top Microbiol Immunol 318:133-75. 2008
    ..This review will focus on evidence regarding the potential physiologic role of those protease families already identified as markers of disease activity in MS; that is, the metallo-, serine, and cysteine proteases...
  2. pmc Critical role for PAR1 in kallikrein 6-mediated oligodendrogliopathy
    Joshua E Burda
    Neurobiology of Disease Program, Mayo Medical and Graduate School, Rochester, Minnesota, USA
    Glia 61:1456-70. 2013
    ....
  3. pmc Kallikrein 6 signals through PAR1 and PAR2 to promote neuron injury and exacerbate glutamate neurotoxicity
    Hyesook Yoon
    Neurobiology of Disease Program, Mayo Medical and Graduate School, Rochester, Minnesota, USA Department of Physical Medicine and Rehabilitation, Mayo Medical and Graduate School, Rochester, Minnesota, USA
    J Neurochem 127:283-98. 2013
    ..Taken together, these data point to a novel Klk6-signaling axis in CNS neurons that is mediated by PAR1 and PAR2 and is positioned to contribute to neurodegeneration...
  4. pmc Activation profiles of human kallikrein-related peptidases by matrix metalloproteinases
    Hyesook Yoon
    Department of Biomedical Sciences, Florida State University, Tallahassee, FL 32306 4300, USA
    Biol Chem 394:137-47. 2013
    ..The results identify MMP-20 as a broad activator of pro-KLKs, suggesting the potential for intersection of the KLK and MMP axes under pathological dysregulation of MMP-20 expression...
  5. pmc Kallikrein 6 is a novel molecular trigger of reactive astrogliosis
    Isobel A Scarisbrick
    Neurobiology of Disease Program, Mayo Medical and Graduate School, Rochester, MN 55905, USA
    Biol Chem 393:355-67. 2012
    ....
  6. pmc Kallikrein 6 regulates early CNS demyelination in a viral model of multiple sclerosis
    Isobel A Scarisbrick
    Neurobiology of Disease Program, Mayo Medical and Graduate School, Rochester, MN, USA
    Brain Pathol 22:709-22. 2012
    ....
  7. pmc Functional role of kallikrein 6 in regulating immune cell survival
    Isobel A Scarisbrick
    Neurobiology of Disease Program, Mayo Medical and Graduate School, Rochester, Minnesota, United States of America
    PLoS ONE 6:e18376. 2011
    ..Herein we specifically examine whether KLK6 alters immune cell survival and the possible mechanism by which this may occur...
  8. pmc Functional intersection of the kallikrein-related peptidases (KLKs) and thrombostasis axis
    Michael Blaber
    Department of Biomedical Sciences, Florida State University, Tallahassee, 32306 4300, USA
    Biol Chem 391:311-20. 2010
    ....
  9. pmc A completed KLK activome profile: investigation of activation profiles of KLK9, 10, and 15
    Hyesook Yoon
    Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306 4300, USA
    Biol Chem 390:373-7. 2009
    ..Conversely, KLK9 and 10, once activated, are unlikely to participate in further pro-KLK activation pathways, although similar to KLK1 they may activate other bioactive peptides...
  10. pmc Protease-activated receptor dependent and independent signaling by kallikreins 1 and 6 in CNS neuron and astroglial cell lines
    Alexander G Vandell
    Molecular Neuroscience Program, Mayo Medical and Graduate School, Rochester, Minnesota 55905, USA
    J Neurochem 107:855-70. 2008
    ....
  11. pmc Activation profiles of human kallikrein-related peptidases by proteases of the thrombostasis axis
    Hyesook Yoon
    Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida 32306 4300, USA
    Protein Sci 17:1998-2007. 2008
    ..The results show that proteases of the thrombostasis family can efficiently activate specific pro-KLKs, demonstrating the potential for important regulatory interactions between these two major protease families...
  12. pmc Kallikreins are associated with secondary progressive multiple sclerosis and promote neurodegeneration
    Isobel A Scarisbrick
    Program for Molecular Neuroscience, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
    Biol Chem 389:739-45. 2008
    ..These novel findings suggest that KLK1 and KLK6 may serve as serological markers of progressive MS and contribute directly to the development of neurological disability by promoting axonal injury and neuron cell death...
  13. pmc Kallikrein cascades in traumatic spinal cord injury: in vitro evidence for roles in axonopathy and neuron degeneration
    Maja Radulovic
    From the Neurobiology of Disease Program MR, JEB, IAS and Departments of Physical Medicine and Rehabilitation HY, NL, JW, RL, IAS and Neurology IAS, Mayo Medical and Graduate School, Rochester, Minnesota Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada EPD Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, Florida SIB, MB and Department of Surgery, Toronto Western Research Institute, Toronto, Ontario, Canada MGF
    J Neuropathol Exp Neurol 72:1072-89. 2013
    ....

Research Grants30

  1. The Shelf Live Evaluation of Investigational Dosage Forms
    Jonathan White; Fiscal Year: 2013
    ..This contract is essential for continued assurance of the quality of drugs undergoing clinical investigation for different types of cancer by Cancer Therapeutics Evaluation Program. ..
  2. p75NTR Ligands for Treament of Traumatic Brain Injury
    Stephen M Massa; Fiscal Year: 2013
    ..The overall goal of this research is to advance the application of these neurotrophic compounds to the treatment of brain trauma and other conditions. ..
  3. Injury and Recovery in Developing Brain
    Flora M Vaccarino; Fiscal Year: 2013
    ..The long-term goal of these studies is to identify new means of therapeutic intervention to decrease the developmental disability and neurobehavioral sequelae of preterm birth. ..
  4. Therapeutic Targeting of Intracellular Mechanisms Involved in Glial Scar Formatio
    Damien D Pearse; Fiscal Year: 2013
    ....
  5. Synaptic Function: Effects of the Nerve Injury, Repair, and Altered Activity
    Timothy C Cope; Fiscal Year: 2013
    ..The Resume and Summary of Discussion above summarizes the final outcome of the group discussion. OVERALL PROGRAM EVALUATION ..
  6. TREM2 regulation of macrophages in spinal cord injury and CNS endogenous repair
    Phillip G Popovich; Fiscal Year: 2013
    ..Moreover, enzyme replacement therapies, using lentiviral transduction of autologous peripheral blood mononuclear cells, were shown to be safe and effective in human subjects. ..
  7. Washington University Intellectual and Developmental Disabilities Research Center
    John N Constantino; Fiscal Year: 2013
    ..WUIDDRC will stimulate advances by creating a collaborative, interdisciplinary environment that will accelerate research to directly impact children with intellectual and developmental disabilities. ..
  8. MOLECULAR ETIOLOGY OF EARLY ONSET TORSION DYSTONIA
    XANDRA OWENS BREAKEFIELD; Fiscal Year: 2013
    ..Nutan Sharma. These integrated studies capitalize on the extensive and complementary expertise of this group focused on the molecular etiology and pathophysiology of early onset dystonia. ..
  9. Center for Novel Therapeutics for HIV-Associated Cognitive Disorders
    Justin C McArthur; Fiscal Year: 2013
    ..5. To identify and validate surrogate biomarkers based on proteomics and lipomics. ..
  10. Regulation of CNS viral persistence
    Cornelia Bergmann; Fiscal Year: 2013
    ..Importantly, it will provide valuable information on the interactions of specific CNS cells involved in viral persistence and demyelination and the cellular and soluble mediators of the host immune response...
  11. Activity-dependent functional regeneration after SCI and OEC transplantation
    PATRICIA EMORY PHELPS; Fiscal Year: 2013
    ..Ultimately, such mechanisms may be among the best candidates to enhance the functional benefits derived from OEC transplantation in completely paralyzed SCI patients. ..
  12. Center for Integrative Neuroscience
    Michael A Webster; Fiscal Year: 2013
    ..abstract_text> ..
  13. Transcriptome analysis of glia responding to injury
    SEAN DAVID SPEESE; Fiscal Year: 2013
    ....
  14. Restoring Iron Homeostasis to Promote Recovery after Spinal Cord Injury
    Dana M McTigue; Fiscal Year: 2013
    ..By doing so, new pharmacologic or genetic interventions can be customized to promote efficient neurological recovery without causing systemic pathology. ..
  15. GENE THERAPY FOR METABOLIC DISORDERS
    Chester B Whitley; Fiscal Year: 2013
    ..abstract_text> ..
  16. 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. ..
  17. CYTOKINES IN GLIAL CELLS AND EAE BRAIN
    Inderjit Singh; Fiscal Year: 2013
    ..These studies will identify therapeutic targets for induction of myelin repair in MS and these findings should be applicable to other related neurodegenerative diseases. ..
  18. Tissue injury and inflammation in MS (P50)
    Bruce D Trapp; Fiscal Year: 2013
    ..abstract_text> ..
  19. Lymphocyte Functions in the Injured Spinal Cord
    Phillip G Popovich; Fiscal Year: 2013
    ..Data from these studies will be used to develop novel clinical therapies to treat SCI in humans. ..
  20. Plasticity and Repair in the Phrenic Motor System
    Paul J Reier; Fiscal Year: 2013
    ..gray matter contributions to other SCI-related functional outcomes. ..
  21. Mechanisms of secondary injury after SCI
    Jacqueline C Bresnahan; Fiscal Year: 2013
    ....
  22. Molecular Mechanisms linking Aging, Abeta Proteotoxicity and Neurodegeneration
    Jeffery W Kelly; Fiscal Year: 2013
    ..abstract_text> ..
  23. Trauma to Developing Brain-Injury and Repair Mechanisms
    Linda J Noble; Fiscal Year: 2013
    ..Together, these studies provide an important foundation for understanding the unique vulnerability of the young brain to TBI and for developing the most appropriate therapies for the brain-injured child. ..
  24. Enhanced EGF Receptor Signaling Prevents White Matter Injury in Perinatal Hypoxia
    Joseph Scafidi; Fiscal Year: 2013
    ..The goal of this project is to promote cellular, metabolic, physiologic and behavior recovery of white matter injury sequelae by enhancing specific signaling pathways of endogenous progenitor cells in the brain. ..
  25. 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. ..
  26. SPINAL CIRCUITS AND THE MUSCULOSKELETAL SYSTEM
    Arthur W English; Fiscal Year: 2013
    ..This PPG brings together a team of established scientists from diverse backgrounds, with a common goal to continue to strengthen the science base underlying clinical rehabilitation. ..
  27. Mechanisms and Interventions for Methamphetamine and HIV-1 Induced CNS Injury
    Yuri Persidsky; Fiscal Year: 2013
    ..abstract_text> ..
  28. TBI-Induced Cerebral Metabolic Depression and Recovery
    David A Hovda; Fiscal Year: 2013
    ..This program project will be housed within the UCLA Brain Injury Research Center (Dr. David A. Hovda, Director) so as to assure appropriate imaging, administrative and laboratory support. ..
  29. Myotonic Dystrophy: Molecular Pathophysiology and CNS Effects
    Laura P W Ranum; Fiscal Year: 2013
    ....