Millions of Americans suffer from neurodegenerative conditions that result from traumatic injury to the brain or spinal cord, stroke, or diseases like multiple sclerosis. Both neurons and glial cells are affected in these conditions. The Sherman lab found that a glycosaminoglycan called hyaluronan (HA), which is found in the extracellular space surrounding cells, plays an important role in the progression of neurodegenerative conditions. A transmembrane glycoprotein called CD44 binds HA and mediates cellular signals that influence cell growth, differentiation and migration. Current research efforts in the Sherman lab aim to determine the efficacy of targeting CD44 and HA to treat neurodegenerative conditions. In addition, members of the Sherman lab are testing how these and other molecules influence neural stem cells that could be used to replace cells in the brain and spinal cord that have been lost due to injury or disease.
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.
Larry Sherman is a Professor in the Division of Neuroscience at ONPRC, and also a Professor in the Department of Cell and Developmental Biology, in the Neuroscience Graduate Program and the Program in Molecular and Cellular Biology at the OHSU School of Medicine. He received a B.A. in 1986 and an M.A. in 1987, both in Biology from Reed College, then went on to receive a Ph.D. in Cell Biology and Anatomy from OHSU in 1993. He conducted post-doctoral research at the Institut für Genetik at the Forschungszentrum in Karlsruhe, Germany, then became an Assistant Professor in the Department of Cell Biology, Neurobiology & Anatomy at the University of Cincinnati School of Medicine in 1998. He joined the center in 2002. He serves on a number of national grant review boards, and is the President of the Oregon Chapter of the Society for Neuroscience.
Back SA, Tuohy TM, Chen H, Wallingford N, Craig A, Struve J, Luo NL, Banine F, Liu Y, Chang A, Trapp BD, Bebo BF Jr, Rao MS, and Sherman LS. (2005) Hyaluronan accumulates in demyelinated lesions and inhibits oligodendrocyte progenitor maturation. Nature Med.11:966-972.
Cargill R, Kohama S, Struve J, Su W, Banine F, Witkowski E, Back SA and Sherman LS. (2012). Reactive astrocytes in aged primate graymatter synthesize excess hyaluronan linked to oligodendrocyte progenitoraccumulation. Neurobiol. Aging 33:830.e13-24.
Preston M, Gong X, Su W, Matsumoto S, Banine F, Winkler C, Foster S, Xing R, Struve J, Dean J, Baggenstoss B, Weigel P, Montine T, Back S and Sherman LS. (2013). Digestion products of the PH20 hyaluronidaseinhibit remyelination. Ann. Neurol. 73:266-80.
Raber J, Olsen RHJ, Su W, Foster S, Xing R, Acevedo S and Sherman LS. (2014). CD44 is required for spatial memory retention and sensorimotor functions. Behav. Brain. Res. 275C:146-149.
Matsumoto S, Banine F, Feistel K, Foster S, Xing R, Struve J and Sherman LS. (2016). Brg1 directly regulates Olig2 transcription and is required for oligodendrocyte progenitor specification. Dev. Biol. 413:173-87.
See a full listing of Dr. Sherman's publications.