This is an RCDA application for Dr. Peter W. Baas, who is an Assistant Professor of Anatomy at The University of Wisconsin Medical School. This RCDA, by providing most of the funds required to pay Dr. Baas salary, will free him from a substantial portion of his teaching and departmental responsibilities, thereby permitting him more time to concentrate on his research program. Dr. Baas' long term career goal is to conduct an effective research program on the topic of neuronal development. The research environment at The University of Wisconsin offers state-of-the-art equipment, and great potential for collaboration and assistance from a variety of successful scientists in this and related fields. Through extensive interaction with these colleagues over the five-year period of this award, Dr. Baas will learn new techniques that will significantly enhance his ability to address important questions on the topic of neuronal development. The overall goal of the present research plan is to study the mechanisms by which microtubules are regulated during axon growth. Neurons extend axons over long distances to reach their target tissues during normal development and also during regeneration following injury. Microtubules provide the architectural framework of the axon, and organize the cytoplasm within the axon to carry out essential motile and metabolic processes. Several lines of evidence indicate that axon growth involves the assembly of new microtubules followed by their stabilization and incorporation into the stable cytoskeleton of the axon. No direct data exist which indicate where microtubule assembly and stabilization occur in growing axons, nor how these processes are regulated. Resolution of these issues is essential for elucidating how the microtubule framework of the axon is generated during axon growth. Indirect evidence indicates that microtubule assembly in the axon is regulated by discrete nucleating structures. Major goals of this application are determine the identity and distribution of these nucleating structures. Other goals are to determine where in the axon newly assembled microtubules become stabilized, and how this stabilization occurs. These experiments involve direct visualization of newly assembled and stable microtubules of the axon using both quantitative immunofluorescence and immunoelectron microscopy. Successful completion of the proposed experiments will resolve several issues concerning the spatial regulation of microtubule assembly and stabilization during axon growth. This information will further current understanding of the cellular and molecular processes that contribute to neuronal development and plasticity, and may provide clues to the cellular defects that underlie the cytoskeletal abnormalities associated with degenerative pathologies of the nervous system.
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