The proposed research is a continuation of ongoing studies of the role of the cellular milieu in regulating neuronal growth, development and responses to injury. The studies focus on mechanisms mediating interactions between neurons and Schwann cells in developing sympathetic superior cervical ganglion (SCG). The first group of studies examine the role of the transforming growth factor B (TGFb) family of cytokines in regulating ganglion development. Specifically, the proposed studies examine the manner in which this family of factors influences the phenotype of both neurons and Schwann cells and how other factors involved in ganglion development are regulated by the TGFb family. TGFb regulation of expression of leukemia inhibitory factor (LIF), neurotrophins, and glial growth factor (GGF) in the SCG will be examined. The role of the TGFb subfamily, the bone morphogenetic proteins, in regulating sympathetic cholinergic development will be defined. Finally, expression of the TGFb cytokines and their receptors in the SCG will be examined to help define their normal role in vivo. The second group of studies will define mechanisms mediating developmental changes in growth factor function. Specifically, treatment of cultured sympathetic ncurons with LIF or with ciliary neurotrophic factor (CNTF) induces apoptosis of neonatal neurons, but promotes survival of neurons after postnatal day 8. The proposed studies examine developmental changes in signal transduction mechanisms which mediate this switch in the effects of LIF and CNTF. In a broad sense these studies seek to define the mechanisms mediating neuronal-glial interactions in the developing peripheral nervous system, and the molecular basis of phenotypic plasticity. The applicant hopes that these studies will indicate biochemical loci where therapeutic intervention in disease processes may lead to normal neuronal function.
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