Spinal cord injury frequently results in permanent disruption of sensory and motor pathways and irreversible functional loss due to the inability of axons in the central nervous system to regenerate. Studies of spinal injury reported during the last decade suggest that inhibitory signals in injured spinal cord tissue contribute to regeneration failure. The identities of these inhibitory signals are largely unknown. Efforts to understand axon guidance during development have led to the identification of many axon-repellent molecules. These proteins belong to a small number of gene families. One such gene family is the semaphorins. Recently published studies suggest semaphorins may play a role in adult animals as well. These demonstrated that the expression of Semaphorin3A, a type 3 secreted semaphorin, is up-regulated in response to central nervous system injury. In addition, adult sensory neurons are repelled by secreted semaphorins. The goal of this application is to begin testing the hypothesis that secreted semaphorins contribute to regeneration failure after spinal cord injury. In addition, this application is designed to advance our understanding of the relationship between semaphorin structures and their inhibitory functions.
The specific aims are: 1) To identify elements of the activation domain of semaphorin 3A using several complementary approaches including chimeric proteins, deletion analysis, point mutations, inhibitory peptides and blocking antibodies. 2) To develop a reagent which inhibits all secreted semaphorins. This strategy may allow identification of novel biological roles for semaphorins since multiple secreted semaphorins may participate in each function and compensate for each other. 3) To examine whether secreted semaphorins contribute to regeneration failure within the adult spinal cord. This work will improve our understanding of the structure function relationship of the secreted semaphorins. This work should also advance our knowledge of the response to injury in the adult central nervous system.
