Himanshu Sharma
B.S. Case Western University, 2011

2nd Year Medical Student

Advisor: TBD

Department: School of Medicine

Graduate Program: TBD

Title:  MMP modification of ECM molecules influences oligodendrocyte maturation, migration, and development in the rat SVZ

Advisor: Holly Colognato, Ph.D, Pharmacological Sciences, Stony Brook University

Abstract (rotation):

          Extracellular matrix molecules (ECM) have been implicated to play a role in the process of myelination by regulating oligodendrocyte development, migration, and maturation. In particular, laminin has been shown to be crucial for gliogenesis, by regulating oligodendrocyte precursor development and maturation. Laminins, among other ECM components, can be cleaved by a family of proteases known collectively as Matrix Metalloproteinases (MMPs). By cleaving ECM, MMPs can therefore change the signaling profiles of ECM components.

          We decided to test the hypothesis that MMPs are involved in gliogenesis in a specific part of the brain known as the subventricular zone, where newborn oligodendrocyte precursors arise from stem cells. In particular, we predict that MMP cleavage of laminins found in the subventricular zone could change the ability of laminin to regulate oligodendrocyte development. We examined subventricular zone tissue for the expression of MMPs at various timepoints during postnatal development by isolating and amplifying RNA transcripts for MMPs 7, 9, and 14. We also tested whether MMP-7 could cleave a subtype of laminin known to be present in the brain. Finally, in a neurosphere model of gliogenesis we tested the broad spectrum MMP inhibitor GM6001 and its effect on glial progenitor differentiation into oligodendrocyte or other cell types. Preliminary results indicate that MMP-7 can indeed cleave laminin-1 and that several MMPs are preferentially expressed in the SVZ in a location and time-dependent manner. Furthermore, there appear to be subtle differences in the cell fate of plated neurospheres when MMP activity is inhibited. In summary, while more work needs to be done, there is evidence that MMPs do play a role in modifying the ECM during gliogenesis, and that their impact on oligodendrocyte development may be, at least in part, by modulating laminin’s ability to regulate cell fate choices.

Publications:
(pre-MSTP publications indicated with an *)

*Sharma H, Alilain WJ, Sadhu A, Silver J. (2012). Treatments to restore respiratory function after spinal cord injury and their implications for regeneration, plasticity and adaptation. Exp Neurol. 235:18-25.