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Faculty
 Stephen
J. Crocker
Assistant Professor, Neuroscience
crocker@uchc.edu
- B.S., University of King's College
- Ph.D., University of Ottawa
- Neuroscience Graduate Program
- Accepting lab rotation students: Fall '08, Spring '09
Areas of Interest:
Stem cells; glia; metalloproteinases; cytokines; development;
pathology; tissue culture.
My lab is interested in how the immune and nervous systems interact
and how this balance is disrupted in diseases of the nervous system. The
ultimate aim of our research program is to understand how the brain is
injured during chronic inflammatory diseases of the nervous system, what
regulates the ability of the brain to repair itself and how this
knowledge might be used to promote brain regeneration and recovery.
Our current projects are examining role of the immune system in
myelin pathology as it relates to diseases like Multiple Sclerosis (MS).
In MS, the immune system mounts an inappropriate response against the
coating of the nerve cells, called myelin. Myelin is critical for proper
brain development and function. Hence, progressive myelin injury in MS
can result in debilitation that can lead to permanent disability. The
cause of MS is not known.
The purpose of this research is to understand how the nervous system
responds to myelin injury and repairs myelin damage. Toward this goal,
we have found that during an inflammatory attack that causes myelin
damage the nervous system produces a protein called Tissue Inhibitor of
Metalloproteinases-1 (TIMP-1). A function of TIMP-1 is to block key
enzymes, called metalloproteinases, immune cells use to move into the
brain tissues and can breakdown myelin. Our studies indicate that during
inflammatory models of myelin injury TIMP-1 may be important in the
regulation of immune cells called macrophages and microglia. As well, we
determined that following myelin injury mice that lack TIMP-1 are also
less able to repair their myelin. Accordingly, we propose to study two
primary functions we believe to be important roles for TIMP-1: the
control of macrophages and microglia following myelin injury, and the
stimulation of myelin repair through promoting endogenous cells to
rebuild the injured myelin.
It is interesting to note that although basal expression of TIMP-1 in
the adult CNS is very low, it is readily and consistently induced in a
variety of rodent demyelination models and increased in human
individuals with acute demyelinating encephalomyelitis. However, levels
of TIMP-1 are not elevated in chronic progressive forms of MS. It is
plausible that chronic CNS inflammation, as occurs in MS, attenuates the
ability of the brain to express TIMP-1 and the down-regulation of TIMP-1
may contribute to an individual’s susceptibility to developing CNS
demyelination. Indeed, a paucity of TIMP-1 has also been reported with a
chronic virus infection of the brain. Accordingly, we propose that study
of TIMP-1 may represent an important system to understand MS-related CNS
pathology.
Lab Rotation Projects:
Research rotation projects in the lab will address the following
questions:
Project 1. Does TIMP-1 participate in the regulation of CNS
myelination?
Project 2. How does TIMP-1 regulate microglial responses to injury?
Project 3. What controls astrocytic TIMP-1 expression?
Selected Publications:
S.J. Crocker, R.F. Frausto, J.K. Whitmire, N.J. Benning, R. Milner,
J.L. Whitton (2007) Amelioration of coxsackievirus B3 mediated
myocarditis by inhibition of TIMP-1. Am. J. Pathol. 171, 1762-73.
R.F. Frausto, S.J. Crocker, B. Eam, J.K. Whitmire, J.L. Whitton
(2007) Myelin oligodendrocyte glycoprotein peptide-induced experimental
allergic encephalomyelitis and T cell responses are unaffected by
immunoproteasome deficiency. J. Neuroimmunol. 192, 124-33.
S.J. Crocker, J.K. Whitmire, R.F. Frausto, P. Chertboonmuang, P.D.
Soloway, J.L. Whitton, I.L. Campbell (2006) Persistent Macrophage/Microglial
Activation and Myelin Disruption following Experimental Autoimmune
Encephalomyelitis in TIMP-1 Deficient Mice. Am. J. Pathol. 169, 2104-16.
S.J. Crocker, R. Milner, N.Pham-Mitchell, I.L. Campbell (2006) Cell
and Agonist-specific Expression of Genes for Matrix Metalloproteinases (MMPs)
and their Tissue Inhibitors (TIMPs) by Primary Glial Cells. J. Neurochem.
98, 812-823.
S. Kalia, S. Lee, L. Liu, S.J. Crocker, T.E. Thorarinsdottir, P.D.
Smith, J. Glover, E.A. Fon, D.S. Park, A.M. Lozano (2004) Bag-5 inhibits
Parkin and enhances dopaminergic neuron degeneration. Neuron 44(6):
931-45.
S.J. Crocker, A. Pagenstecher, I.L. Campbell (2004) The TIMPs Tango
with the MMPs and more in the CNS. Journal of Neuroscience Research
75(1):1-11.
P.D. Smith, S.J. Crocker, V. Jackson-Lewis, S.M. Callaghan, R.S.
Slack, S.P. Hayley, S. Przedborski, H. Anisman, D.S. Park (2003)
Inhibition of cyclin-dependent kinases prevents dopamine neuron
degeneration and locomotor deficits in an MPTP mouse model of
Parkinson’s Disease. Proceedings of the National Academy of Sciences
(USA) Track II, 100(23):13650-5.
S.J. Crocker, P.D. Smith, V. Jackson-Lewis, W.R. Lamba, E. Melloni,
S.M. Callaghan, S. Przedborski, E. Grimm, G.S. Robertson, H. Anisman, Z.
Merali, D.S. Park (2003) Inhibition of Calpains Prevents Neuronal and
Behavioural Deficits in an MPTP Mouse Model of Parkinson’s disease.
Journal of Neuroscience 23(10): 4081-4091.
S.J. Crocker, W.R. Lamba, P.D. Smith, S.M. Callaghan, R.S. Slack, H.
Anisman, D.S. Park (2001) c-Jun mediates axotomy-induced dopamine
neurons death in vivo. Proceedings of the National Academy of Sciences
(USA) Track II, 98(23): 13385-13390.
S.J. Crocker, N. Wigle, P. Liston, C.S. Thompson, C.J. Lee, D.G. Xu,
S. Roy, D.W. Nicholson, D.S. Park, A. MacKenzie, R.G. Korneluk, G.S.
Robertson (2001) NAIP Protects the Nigrostriatal Dopamine Pathway in an
adult intrastriatal 6-OHDA model of Parkinson’s disease. European
Journal of Neuroscience 14(2):391-400.
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