Target regulation of neuronal plasticity

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Considerable progress has been made in identifying factors that play important roles in regulating neuronal plasticity, both during development and in maturity. The PI has been actively studying one example of such plasticity, i.e., the growth of mature sympathetic axons into the injured CMS, using a variety of in vivo and in vitro manipulations. A dramatic example of "natural" plasticity is the response of uterine sympathetic nerves to changes in circulating levels of sex hormones. Uterine sympathetic nerves show constant phases of degeneration and regeneration during the natural estrous cycle, reflecting fluctuations in circulating levels of estrogen. Remarkably, the uterine sympathetic terminal plexus degenerates completely during normal pregnancy and regenerates after parturition. Failure of this "natural" plasticity occurs in pathological situations such as pre-eclampsia, which can be fatal to both mother and fetus. The cause(s) of pre- eclampsia are unknown, but persistent sympathetic innervation may contribute by inducing vasoconstriction. In the case of uterine leiomyomas (fibroids), which are sex hormone-sensitive benign myometrial tumors that occur in up to 77% of women of reproductive age, sympathetic nerves are absent. In fact, fibroids resemble the pregnant myometrium in both the absence of autonomic nerves and the enrichment of extracellular matrix (ECM) components. The mechanisms underlying plasticity in uterine sympathetic nerves are not fully understood, but available evidence indicates that such plasticity reflects changes in the balance between growth-promoting and growth-inhibiting substances in the target, as well as hormone-induced changes in the receptivity of uterine-projecting sympathetic neurons. Preliminary studies indicate that uterine substrate- bound signals are likely to contribute to plasticity in uterine sympathetic nerves.The goals of the present proposal are: (1) to establish the contribution of substrate-bound signals to the "natural" plasticity of the uterine sympathetic innervation; (b) to explore the role of substrate-bound signals in regulating sympathetic innervation in pre-eclampsia and uterine leiomyoma; (3) and to assess the interaction of sex hormones and neurotrophins with uterine substrate-bound signals in regulating innervation. The proposed work is a collaborative effort to be conducted primarily at the Institute de Investigaciones Biol6gicas Clemente Estable in Montevideo, Uruguay with Dr. Monica Brauer as an extension of NIH grant #R01NS044972.