Traumatic injury of the spinal cord in humans leads to permanent paralysis and other serious medical complications. Paralysis is a result of lost neuronal connectivity between the brain and spinal cord motor units. The failure of severed spinal axons to recover, however, is not primarily due to an intrinsic inability to regenerate, but is a result of the central nervous system (CNS) environment that is highly refractory to axonal growth. When provided with a suitable environment, injured CNS axons do recover, extending processes over long distances and partially restoring function in animal models of spinal cord injury (SCI). Multiple CNS myelin constituents are thought to directly contribute to the regenerative failure of damaged spinal axons, including proteins called Nogo, myelin-associated glycoprotein (MAG), and oligodendrocyte-myelin glycoprotein (OMgp). The main objective of this study is to gain insights into the molecular and cellular mechanisms of myelin-mediated inhibition of axonal growth. A detailed understanding of the biology of axon-glia interaction is a prerequisite to devising strategies aimed at lowering the growth inhibitory barrier of adult CNS myelin and to promote neuronal repair following traumatic injury of the CNS. The identification, of a novel family of receptor proteins comprised of members with distinct binding specificities toward established myelin inhibitors of axonal growth is at the heart of our investigations. A major goal of the proposed study is to define the role of these receptors in neuronal responses to CNS myelin inhibitors. To functionally characterize members of this gene family, we will engineer recombinant viral vectors for gain-of-function studies in neurons. Mouse genetics will be used for loss-of-function studies in vivo. In a parallel approach, we will develop mutated receptors with antagonistic function. Mutated soluble receptors that still bind ligand but no longer possess the ability to signal axonal growth inhibition will be assessed for their potential to promote axonal growth on myelin substrate in vitro. Coupling our biochemical approaches with in vitro neurite outgrowth assays and in vivo functional studies will provide a strong basis to elucidate the role played by novel receptor-ligand interactions in neurite outgrowth inhibition. Together, this family of receptor proteins may provide new molecular handles for the design of therapeutic interventions for CNS injuries.
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