Department of Neurosciences
Case Western Reserve University
School of Medicine E653
My current research focuses on the role of extrinsic factors in guiding developing and regenerating axons along their proper pathways within the brain and spinal cord of mammals. We are particularly interested in studying the cellular and molecular interactions that occur between axonal growth cones and the various types of glial cells that lie along the presumptive routes and at the boundaries of several different fiber systems in the CNS.
We now know that a variety of cell surface and extracellular matrix molecules that stimulate or inhibit axon growth are made by astroglia during a critical period in development. However, as astroglia mature they change dramatically and alter their interactions with growing axons especially following lesions. Thus, following injury in the adult CNS, so-called reactive astroglia actively block rather than promote sustained axonal elongation. We have concentrated our efforts over the past several years learning whether the boundary molecules that astroglia make during normal development are re-expressed after injury. One of the most interesting families of extracellular matrix molecules, the proteoglycans, were first discovered by my lab to be major players in creating developmental as well as regenerative boundaries. It is our hope that the understanding of normal and abnormal mechanisms of axon guidance will suggest regeneration strategies for altering or overcoming inhibitory molecules that are made in excess. To this end we have developed a microtransplantation technique which enables us to gently inject fully adult neurons into normal or lesioned white matter tracts of the adult CNS, without causing the formation of additional reactive astroglial associated inhibitory molecules via the transplantation itself. Remarkably, the adult nerve cells can regenerate their axons with high efficiency and at high rates of speed challenging long held beliefs that this is impossible. Importantly, the rapidly regenerating axons halt their growth when they reach the glial scar, providing the strongest evidence to date of the major importance of the proteoglycan laden lesion environment in regeneration failure. We have also developed in vitro assays using gradients of proteoglycans that, like the in vivo glial scar, create dystrophic endings on regenerating adult axons. We can now, for the first time, begin to dissect the molecular and cellular machinery of this unusual axonal ending. Many unanswered and provocative questions remain about the potential for neuronal circuit restoration in the regenerated adult CNS and our lab is now in a strong position to begin answering many of them.
Indeed, we have recently been able to promote robust functional regeneration into the adult rodent spinal cord of severed sensory roots using a combinatorial strategy that maximally stimulates an intrinsic growth response in the sensory neurons while simultaneously removing inhibitory proteoglycans from the cord with a bacterial enzyme (ie., chondroitinase) that removes the inhibitory sugar chains from proteoglycans. An even more exciting development is our recent demonstration that combining an autologous peripheral nervous system “bridge” with inhibitory matrix modification via chondroitinase leads to robust, functional regeneration beyond a hemisection lesion of the adult rat spinal cord. This result, in particular, may have far ranging beneficial clinical consequences. Other labs around the world are now showing that the use of chondroitinase combined with various cell bridging techniques and an enhancement of the neurons intrinsic growth response can restore function in other regeneration models and in other species of mammals. It is highly conceivable that such therapeutic strategies may be useful in restoring both sensory and motor function in paralyzed humans.
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