Richard M. Costanzo, Emeritus - US grants

The proposed project provides a means of studying the unique process of neurogenesis and nerve cell replacement that takes place in the mammalian olfactory system. Chemical and axotomy procedures will be used to induce degeneration of sensory neurons. Subsequent neurogenesis and recovery will be studied using quantitative methods to determine the capacity and limits of this unique process. In addition, an assessment will be made of the importance of target tissue (olfactory bulb) for the replacement of olfactory neurons and the ability of these replacement neurons to re-establish functional connections with the central nervous system. It is expected that data from the proposed study will produce new information which could prove helpful in improving recovery following nerve cell injury. Eventually these studies may lead to methods which could help to repair damaged pathways in the human central nervous system.

Each year over one million Americans suffer from damage or injury to the central nervous system (i.e., head injury, stroke, and brain tumors). In addition, diseases related to aging such as presenile dementia and Alzheimer's Disease are a serious health problem. One of the major goals of basic and clinical research in the Neurosciences is to find new ways to improve recovery and quality of life. The proposed project provides a means of studying the unique process of neurogenesis and nerve cell replacement that takes place in the hamster olfactory system. Two procedures will be used to induce degeneration of sensory neurons: nerve transection and chemical exposure. Subsequent neurogenesis and recovery will be studied using quantitative methods to determine the capacity of replacement neurons to reestablish connections with the central nervous system and to restore function. Recovery after nerve transection will be investigated in: 1) Anatomical studies to determine if replacement neurons have the capacity to restore axon connections to specific target regions in the olfactory bulb, 2) Electrophysiological studies to determine the response of reconnected cells (receptive fields and odor response), and 3) Behavioral studies to determine if animals can detect and respond to sensory stimuli. Recovery from exposure of the nasal cavity to environmental agents (chemicals and metallic dusts) will also be investigated in the hamster. Data from animal experiments will be compared to human autopsy and surgical pathology findings to investigate cellular mechanisms underlying nasal disease. A finding that functional recovery occurs in the hamster olfactory system would suggest that, contrary to current dogma, replacement of neurons and repair of damaged pathways in the mammalian nervous system is possible. This proposal addresses important questions about the potential for neuron replacement and functional repair of damage within the central nervous system. The unique capacity of olfactory neurons for continued neurogenesis provides an excellent model in which to study this process. The results from the proposed experiments could provide a significant breakthrough for the field of neural regeneration and findings may have direct clinical application.

Over one million Americans each year suffer from damage or injury to the central nervous system (ie. head injury, stroke, and brain tumors). In addition, diseases related to aging such as presenile dementia and Alzheimer's Disease are becoming a serious health problem. One of the major goals of basic and clincial research in the Neurosciences is to find new ways to improve recovery and the quality of life. The proposed project provides a means of studying the unique process of neurogenesis and nerve cell replacement that takes place in the mammalian olfactory system. Procedures will be used to induce degeneration of sensory neurons. Subsequent neurogenesis and recovery will be studied using quantitative methods to determine the capacity and limits of this process. Experiments are planned to determine the ability of replacement neuronsto reestablish connections with the central nervous system and restore function. In addition, a group of old animals will be studied to determine if the capacity for neurogenesis and recovery continues into old age. A technique developed for transplanting olfactory neurons into different regions of the CNS will be used to determine the capacity of these neurons to survive in host brain tissue. The persistence of neurogenesis within transplants and the growth of axons into the host brain could hve signficant impact on the field of regeneration. It is expected that data from the proposed study will produce new information about mechanism of neurogenesis and recovery following nerve cell injury. Potentially these studies may lead to methods for the repair of damaged pathways in the human central nervous system.

At present, little hope is offered to those with impaired olfactory function. The long-term objectives of this project are to investigate the mechanisms regulating neural regeneration and to develop strategies to enhance recovery and restore function following injury or disease. An established model of olfactory nerve injury will be used to investigate the role of MMPs following nerve injury and recovery processes during the regeneration and rewiring of olfactory axons in the olfactory bulb. Matrix metalloproteinases (MMPs) are regulators of the extracellular remodeling that occurs in reparative, homeostatic and metastatic processes. This study will determine if MMPs contribute to mechanisms that regulate the response to injury and regenerative and reparative processes in the olfactory system. Changes in MMP levels and their localization within the olfactory bulb will be measured at different time points from the onset of nerve injury, through degeneration, regeneration and recovery. It is hypothesized that MMP9 plays an important role during the early response to injury by regulating the amount of inflammation, gliosis, and scar formation and that MMP2 enhances recovery by facilitating the reinnervation and rewiring of axons in the olfactory bulb. MMP knockout mice will be used to determine if MMPs are required for normal recovery processes. Experiments represent a new direction and a novel approach that will begin to address the mechanisms of olfactory system regeneration and repair at the molecular level. The olfactory system may provide the key to understanding recovery processes in the central nervous system. Findings could lead to the development of new treatment strategies to help improve or restore olfactory function following injury or disease, and lay the groundwork for the future development of treatment strategies directed at modulating the activity of MMPs.