PRESYNAPTIC MECHANISM OF THE LAMBERT-EATON SYNDROME

Lambert-Eaton肌无力综合征（LES）是一种获得性疾病， 神经肌肉传递常与小细胞癌相关 肺的。 这种综合征的缺陷主要是突触前， 其特征在于运动神经末梢不能释放神经递质， 对神经作出反应的乙酰胆碱（ACh）量子的正常数量 冲动 最近的LES临床和实验研究已经取得了很大的进展。 对疾病过程的理解有了相当大的进展。 现在， 被认为是一种自身免疫性疾病， 转移自身抗体已经开发出来，它密切复制了 人类的状况 我们建议的研究的长远目标是了解 负责突触前神经元突触的疾病的突触下机制 研究LES的电生理特性 自身抗体和其明显的突触前抗原识别位点。 我们将追求五个具体目标：（1）进一步表征小鼠 被动转移LES，建立其作为动物模型的有效性;（2） 评价钙敏感性和药理作用 在小鼠LES的过程中，并通过实验验证了减少的假设 Ca 2+内流vs. ACh释放位点减少作为脑缺血的病理生理机制 （3）直接测量突触前缺陷时的内向钙电流， 对照组和小鼠LES运动神经末梢;（4）阐明 机制，其中maitotoxin（MTX）诱导大量增加量子 递质释放;（5）确定LES的体外效应 抗体对大鼠垂体前叶催乳素释放的影响。 的 实验技术包括细胞内和细胞外 记录神经肌肉接头的突触前和突触后事件 和标准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.