The Role of Actomyosin in Response to Injury and Myelin

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DESCRIPTION (provided by applicant): Injury to the nervous system decreases the quality of life of the injured individual. Therefore, it is a priority to develop therapeutic approaches aimed at the amelioration and prevention of damage to the nervous system. The rational development of therapies requires a concrete knowledge of the response of neurons to injury. During injury, nerve fibers are often damaged and respond by retracting. The retraction of nerve fibers results in the loss of connectivity between neuronal populations that manifests as functional disabilities (e.g., loss of motor control and sensation). The retraction of nerve fibers in injured tissue is detrimental to nervous system function and occurs initially in response to direct physical damage, and subsequently in response to myelin-derived inhibitory signals that develop in response to injury. Therefore, it is important to understand the cellular mechanisms involved in nerve fiber retraction in order to develop rational therapeutic approaches. Three aims will be pursued to test the hypothesis that nerve fiber retraction in response to physical injury and myelin-derived inhibitory signals share a common mechanism requiring actomyosin-dependent contractility. Aim 1. Elucidate the role of the cytoskeleton in injury-induced nerve fiber retraction. The cytoskeleton of nerve fibers that have been severed will be studied to determine how it reorganizes in response to injury. The role of actin filaments and microtubules in injury-induced nerve fiber retraction will also be determined. Aim 2. Determine the role of actomyosin contractility in the retraction of severed nerve fibers. A number of techniques will be used to interfere with actomyosin function and study how these treatments affect the retraction of nerve fibers. The role of enzyme systems known to regulate actomyosin function will also be investigated. Aim 3. Determine the role of actomyosin contractility in the response of nerve fibers to myelin-derived inhibitory signals. Similar to aim 2, the effects of inhibiting actomyosin function on myelin-induced axon retraction will be investigated. These studies will use dorsal root ganglion neurons, a population of neurons that sends nerve fibers into the spinal cord. Damage to the nerve fibers of these neurons in the spinal cord can result in the loss of sensation and proprioception. The cellular basis of retraction in vitro will be studied using live video microscopy to directly determine the responses of nerve fibers. A number of methods will be used to inhibit the activity of the actomyosin system, and novel approaches to the inhibition of actomyosin activity will be developed. Collectively, these studies will determine whether the actomyosin system is a viable target for the development of therapies aimed at the inhibition of nerve fiber retraction in injured nervous tissue.