The Sherman lab discovered that a high molecular weight form of HA accumulates in the nervous systems of humans and animals with a number of different neurodegenerative diseases and during the course of normative aging. HA can both control the proliferation of astrocytes, cells that respond to insults to the brain and spinal cord, and act to inhibit the maturation of oligodendrocyte progenitors, which are cells that form the myelin sheaths of central nervous system axons. This latter effect of HA appears to contribute to the failure of remyelination in diseases like multiple sclerosis and in the aging brain. Sherman's hypothesis is that by regulating how this HA accumulates in neurodegenerative conditions and diseases, it may be possible to promote remyelination and nervous system repair.
In addition, Sherman's group is studying how HA, CD44, and other molecules regulate the differentiation of neural stem cells - cells found both during embryonic development and in adults - that can give rise to all of the cell types in the brain and spinal cord. This research is focused on determining whether such cells can be stably expanded and differentiated into the damaged nervous system.
The group has also found that a chromatin remodeling factor, called Brahma-related gene-1 (Brg1), can regulate the expression of neuron and glial cell-type specific genes (including CD44), and that Brg1 may function through a mechanism that includes DNA methylation. These studies are revealing fundamental mechanisms that underlie normal brain development.
Brg1 is part of a larger complex of proteins, called SWI/SNF. Mutations in a gene that encodes another protein in the SWI/SNF complex, called SNF5, are linked to schwannomatosis, a disease characterized by multiple peripheral nerve sheath tumors and intractable pain. Thus, another area of interest in the Sherman lab is to understand how the loss of SWI/SNF activity and SNF5 in particular influences peripheral nerve tumorigenesis and pain.
The long-term aim of all of these studies is to develop experimental therapies for schwannomatosis, demyelinating diseases and related neurodegenerative conditions using both rodent and non-human primate models of these conditions.Read more
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