Following spinal cord injury (SCI), adult mammalian axons initiate a regenerative effort that fails at the site of tissue damage. The local environment at the lesion site is altered as complex cellular responses to injury lead to remodeling of the extracellular matrix (ECM). While there is a general consensus that the environment surrounding the site of injury is inhibitory to axonal growth, the roles of the cellular and ECM components in this process are poorly understood. To begin to address this problem, we have developed a spinal cord contusion injury model in the mouse, and we have compared ECM and axon profile distribution in selected inbred strains of mice that differ in the cellular response to an identical injury paradigm. Our preliminary data indicate that the cellular and ECM composition at the lesion dictate the distribution and extent of axonal growth after a contusive SCI. For example, we observed increased axonal growth in strains with a reduced expression of chondroitin sulfate proteoglycan sidechains, or CSPG-GAGs, in the glial borders of the lesion and increased laminin within the lesion site. To extend and test this central hypothesis, we will complete the following four specific aims:
In Specific Aim 1, we will determine the distribution and trajectory of identified axons approaching the site of contusion injury in chosen inbred mouse strains. Using the phenotypic variation in cellular response to injury as a tool, we will define the distribution of axons in and around the lesion site with immunohistochemical and anterograde tract tracing methods. These experiments will serve to identify the strains and regions that are associated with growing axons. Then, we will study those regions further in Specific Aim 2 to define the relationship between axon profiles, supporting cells, and ECM components at the lesion site. These experiments will center on co-localizing axons with cellular and ECM components, including CSPGs and laminins, using light, confocal, and electron microscopy.
In Specific Aim 3, we will directly test the role of CSPG-GAGs on axonal growth in and around the site of a contusion injury, using chondroitinase ABC to cleave the GAG sidechains from the core proteins. Finally, in Specific Aim 4, we will extend the study of axon/ECM interactions to determine the role of the local ECM on the integration and growth of embryonic neurons after transplantation into the site of a contusion lesion. Together, these four aims will establish a firm basis for understanding the relationship between cellular and ECM remodeling and axonal growth after SCI, and will help to direct future strategies to enhance axonal growth after injury.
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