Target regulation of neuronal plasticity

描述(由申请人提供)：在确定在发育和成熟过程中对神经元可塑性起重要作用的因素方面已经取得了相当大的进展。PI一直在积极研究这种可塑性的一个例子，即成熟的交感神经轴突生长到受损的中枢神经系统，使用各种体内和体外操作。“自然”可塑性的一个戏剧性例子是子宫交感神经对循环中性激素水平变化的反应。子宫交感神经在自然发情周期中表现出持续的退化和再生阶段，反映出循环中雌激素水平的波动。值得注意的是，子宫交感神经末梢丛在正常妊娠期间完全退化，分娩后再生。这种“自然”可塑性的丧失会发生在病理性的情况下，比如先兆子痫，这可能会对母亲和胎儿都是致命的。先兆子痫的病因(S)尚不清楚，但持续的交感神经支配可能通过诱导血管收缩而起作用。子宫肌瘤(肌瘤)是一种性激素敏感型良性子宫肌层肿瘤，发生在77%的育龄妇女中，交感神经缺失。事实上，子宫肌瘤类似于妊娠子宫肌层，既没有自主神经，也有丰富的细胞外基质(ECM)成分。子宫交感神经可塑性的机制尚不完全清楚，但现有证据表明，这种可塑性反映了靶区促生长物质和生长抑制物质之间平衡的变化，以及激素诱导的子宫交感神经投射神经元感受性的变化。初步研究表明，子宫底物结合信号可能有助于子宫交感神经的可塑性。本研究的目标是：(1)确定底物结合信号对子宫交感神经“自然”可塑性的贡献；(B)探讨底物结合信号在子痫前期和子宫肌瘤交感神经调节中的作用；(3)评估性激素和神经营养因子与子宫底物结合信号在调节交感神经支配中的相互作用。拟议的工作是一项合作努力，将主要在乌拉圭蒙得维的亚的克莱门特·埃斯特布尔生物研究所与莫妮卡·布劳尔博士合作，作为国家卫生研究院#R01NS044972号赠款的延伸。

DESCRIPTION (provided by applicant): 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 CNS, 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 Biologicas Clemente Estable in Montevideo, Uruguay with Dr. Monica Brauer as an extension of NIH grant #R01NS044972.