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.
Revised March, 2008. |
