Role of Protease Activated Receptors in Spinal Cord Injury and Repair
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
- The multiple sclerosis degradome: enzymatic cascades in development and progression of central nervous system inflammatory diseaseI 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...
- Critical role for PAR1 in kallikrein 6-mediated oligodendrogliopathyJoshua E Burda
Neurobiology of Disease Program, Mayo Medical and Graduate School, Rochester, Minnesota, USA
Glia 61:1456-70. 2013....
- Kallikrein 6 signals through PAR1 and PAR2 to promote neuron injury and exacerbate glutamate neurotoxicityHyesook 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...
- Activation profiles of human kallikrein-related peptidases by matrix metalloproteinasesHyesook 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...
- Kallikrein 6 is a novel molecular trigger of reactive astrogliosisIsobel A Scarisbrick
Neurobiology of Disease Program, Mayo Medical and Graduate School, Rochester, MN 55905, USA
Biol Chem 393:355-67. 2012....
- Kallikrein 6 regulates early CNS demyelination in a viral model of multiple sclerosisIsobel A Scarisbrick
Neurobiology of Disease Program, Mayo Medical and Graduate School, Rochester, MN, USA
Brain Pathol 22:709-22. 2012....
- Functional role of kallikrein 6 in regulating immune cell survivalIsobel 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...
- Functional intersection of the kallikrein-related peptidases (KLKs) and thrombostasis axisMichael Blaber
Department of Biomedical Sciences, Florida State University, Tallahassee, 32306 4300, USA
Biol Chem 391:311-20. 2010....
- A completed KLK activome profile: investigation of activation profiles of KLK9, 10, and 15Hyesook 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...
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Molecular Neuroscience Program, Mayo Medical and Graduate School, Rochester, Minnesota 55905, USA
J Neurochem 107:855-70. 2008....
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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...
- Kallikreins are associated with secondary progressive multiple sclerosis and promote neurodegenerationIsobel 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...
- Kallikrein cascades in traumatic spinal cord injury: in vitro evidence for roles in axonopathy and neuron degenerationMaja 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
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