PRESYNAPTIC MECHANISM OF THE LAMBERT-EATON SYNDROME

Lambert-Eaton肌无力综合征(LES)是一种获得性疾病 常与小细胞癌相关的神经肌肉传递 肺脏的。这种综合征的缺陷主要是突触前， 其特点是运动神经末梢不能释放 正常数量的乙酰胆碱(ACh)对神经的反应 冲动。最近对LES的临床和实验研究取得了 在理解疾病过程方面取得了相当大的进展。莱斯现在是 一种被认为是一种自身免疫性疾病的动物模型 转移的自身抗体已经被开发出来，它紧密地复制了 人类的状况。 我们建议进行的研究的长远目标是要了解 突触前疾病的突触下机制 LES损伤及电生理特性的研究 自身抗体及其突触前抗原识别表观部位。 我们将追求五个具体目标：(1)进一步表征小鼠 被动移植LES及其作为动物模型的有效性； 终末期释药的钙敏感性和药理学评价 在小鼠LES中的过程，并从实验上验证了简化的假设 钙离子进入与ACh释放部位减少的关系及其病理生理机制 突触前缺损区；(3)直接测量 对照和小鼠LES运动神经末梢；(4)阐明 巨噬细胞毒素(MTX)诱导细胞数量大量增加的机制 递质释放；以及(5)测定LES的体外效应 抗大鼠垂体前叶催乳素释放的抗体。这个 将使用的实验技术包括细胞内和细胞外 神经肌肉接头突触前、后事件的记录 和标准的双抗体放射免疫测定法来完成 激素浓度的测定。

Lambert-Eaton myasthenic syndrome (LES) is an acquired disorder of neuromuscular transmission frequently associated with small-cell carcinoma of the lung. The defect in this syndrome is primarily presynaptic, characterized by an inability of the motor nerve terminals to release a normal number of acetylcholine (ACh) quanta in response to a nerve impulse. Recent clinical and experimental studies of LES have achieved a sizeable advance toward understanding of the disease process. LES is now recognized as an autoimmune disease and an animal model based on passively transferred autoantibodies has been developed, which closely reproduces the human condition. The long-term objectives of our proposed study are to understand the subsynaptic mechanisms of the disease responsible for presynaptic impairment and to study the electrophysiological characteristics of LES autoantibodies and their apparent presynaptic antigenic recognition sites. We will pursue five specific aims: (1) further characterize the murine passive transferred LES and establish its validity as an animal model; (2) evaluate the Ca2+ sensitivity and pharmacology of the termial release process in murine LES and experimentally verify the hypothesis of reduced Ca2+ entry vs. reduced ACh release sites as a pathophysiologic mechanism of the presynaptic defect; (3) directly measure the inward Ca2+ currents at the control and murine LES motor nerve terminals; (4) elucidate the mechanism by which maitotoxin (MTX) induces a massive increase of quantal transmitter release; and (5) determine the in vitro effects of LES antibodies on prolactin release from rat anterior pituitary glands. The experimental techniques to be used include intra- and extracellular recording of the pre- and postsynaptic events of the neuromuscular junction and standard double antibody radioimmunoassay to accomplish the determination of hormone concentration.