Research Projects

TIMP-1 Regulation of Oligodendrogenesis

Tissue inhibitor of matrix metalloproteinases-1 (TIMP-1) is a protein secreted by astrocytes that we have recently determined to be a novel trophic factor for oligodendrocyte progenitor cells (Moore et al, 2011; Moore and Crocker, 2012). We hypothesize that the lack of this protein in people with multiple sclerosis contributes to chronic myelin pathology in this disease. We are presently studying the functional contribution of astrocytic production of TIMP-1 in a variety of neurodegenerative and demyelinating disease models. This work was funded by a Career Transition Award from the National Multiple Sclerosis Society.

Induced Pluripotent Stem (iPS) Cells in Multiple Sclerosis

Primary Progressive Multiple Sclerosis (PPMS) is an aggressive debilitating unremitting type of multiple sclerosis. We hypothesize that myelin pathology in PPMS arises from an inherent defect in the myelinating potential of the oligodendrocytes. To test this idea we have been funded by the State of Connecticut Stem Cell Fund to develop novel iPS cell lines from individual with PPMS to allow us to study the behaviour of these cells and their propensity to make myelin (Crocker et al., 2011).

MMP-3 Regulation of Microglia

Matrix metalloproteinases (MMPs) are extracellular proteases involved in tissue development and homeostasis. In diseases, expression and activity of MMPs can develop discordance that results in tissue pathology. We have been studying the role of MMPs in genetic demyelinating diseases, called leukodystrophies. Specifically, we have determined that MMP-3 is dramatically up-regulated in an often fatal condition called globoid cell leukodystrophy, or Krabbe disease (Ijichi et al., 2013). This novel role for MMP-3 in this disease we determined is to activate the resident immune cells of the brain, called microglia. MMP-3, when induced by the toxin psychosine, transforms microglia into a particular type of multi-nucleated "globoid cell", which is a characteristic pathology of this disease. We hypothesize that the proteolytic activation and formation of globoid cells by MMP-3 is related to the development of myelin pathology in GLD.