US-France Cooperative Research: Localization & Regulation of Cell Adhesion Molecules & Substrate Adhesion Molecules During Development & Regeneration of the Neuromuscular Sys

该奖项将支持洛克菲勒大学神经科学研究所的Gerald Edelman博士和他的研究小组与法国巴黎国家Recherche Science中心Unite de Recherche de Biologie et病理神经肌学家Francois Rieger博士之间的合作研究。埃德尔曼博士是诺贝尔奖获得者，也是这一提议课题的杰出研究人员，他过去曾与里格博士成功合作。神经肌肉系统是一个复杂的超细胞结构，由许多不同类型的细胞组成：感觉和运动神经元、雪旺细胞、肌肉细胞、成纤维细胞和各种支持细胞。神经肌肉系统的发育、维持和生理功能依赖于特殊的结构，包括神经肌肉连接、肌腱连接和Ranvier结节。在以前的研究中，Edelman和Rieger博士证明了参与细胞-细胞黏附的三种糖蛋白定位于这些特权位置，并且在神经肌肉接触的发展和再生过程中数量和分布不同：神经细胞黏附分子N-CAM、神经元-神经胶质细胞黏附分子Ng-CAM和细胞外基质蛋白Cytoactin。在具有各种细胞缺陷的突变动物中，这些分子的定位发生了改变，N-CAM抗体阻断了损伤后适当的再神经支配模式，抑制了旧突触位置的突触重建，并允许突触外神经-肌肉接触。这些分子的表达模式与其他神经肌肉蛋白的表达模式相关，包括乙酰胆碱酯酶和电压依赖性钙通道。在下一阶段的合作中，研究人员将检查黏附分子和神经肌肉蛋白局部表达模式的详细基础，特别是细胞骨架相互作用。他们还将使用针对肌肉形式的N-CAM的cdna克隆来转染细胞并产生转基因动物。这些联合实验单独在任何一个实验室都很难完成。Rieger博士和他的同事在电子显微镜、神经生理学和小鼠突变株方面的专业知识将补充Edelman博士和他的团队在细胞黏附分子的分离和表征、分子生物学技术、荧光显微镜以及单克隆和多克隆抗体的生产和筛选方面的专业知识。这些研究应该为肌肉功能关键结构的形成和维持，以及它们在肌肉疾病和功能障碍中的异常提供新的见解。

This award will support collaborative studies between Dr. Gerald Edelman and his research group at the Neurosciences Institute, Rockefeller University and Dr. Francois Rieger, Unite de Recherche de Biologie et Pathologie Neuromusculaires, Centre National de la Recherche Scientifique, Paris, France. Dr. Edelman, a Nobel Prize winner and eminent researcher in the proposed topic, has collaborated successfully with Dr. Rieger in the past. The neuromuscular system is a complex supracellular structure composed of a number of different cell types: sensory and motor neurons, Schwann cells, muscle cells, fibroblasts, and various support cells. The development, maintenance, and physiological functions of the neuromuscular system depend upon specialized structures, including the neuromuscular junction, the myotendinous junction, and the nodes of Ranvier. In previous research Drs. Edelman and Rieger showed that three glycoproteins involved in cell-cell adhesion are localized to these privileged sites and vary in amount and distribution during development and regeneration of neuromuscular contacts: the neural cell adhesion molecule, N-CAM, the neuron-glia cell adhesion molecule, Ng-CAM, and cytotactin, an extracellular matrix protein. The localization of these molecules was altered in mutant animals with various cellular defects and antibodies to N-CAM blocked the appropriate reinnervation patterns after injury, inhibiting reformation of synapses at old synaptic sites and allowing for extrasynaptic nerve-muscle contacts. The patterns of expression of these molecules correlate with those of other neuromuscular proteins, including acetylcholinesterase, and voltage-dependent calcium channels. During the next phase of collaboration, the investigators will examine the detailed basis for the localized pattern of expression of adhesion molecules and neuromuscular proteins, focusing particularly on cytoskeletal interactions. They will also use cDNA clones specific for muscle forms of N-CAM to transfect cells and produce transgenic animals. These joint experiments would be difficult to accomplish in either laboratory alone. The expertise of Dr. Rieger and his colleagues in electron microscopy, neurophysiology and mutant strains of mice will complement the expertise of Dr. Edelman and his group in the isolation and characterization of cell adhesion molecules, molecular biological techniques, fluorescence microscopy and the production and screening of monoclonal and polyclonal antibodies. These studies should provide new insights into the formation and maintenance of structures crucial to muscle function, as well as to their aberrations in muscle disease and dysfunction.