APP & MOTONEURON DEATH: PEDIATRIC CNS INJURY

简介(改编自申请人的摘要)：中环发展 神经系统(CNS)包括组织发生、分化、 迁移、细胞相互作用(包括传入细胞、靶细胞、周围细胞) 和细胞死亡。许多个体因素在中枢神经系统的发育中起着关键作用 包括细胞外基质分子、营养因子、细胞因子和 单个蜂窝组件。因素和细胞的相互作用确保了 上述发育事件导致了功能性的、成熟的 中枢神经系统。对这些事件的研究不仅有助于我们理解 发展过程，但也为理解 病态病理状态，尤指出现在脑部疾病中的 儿科中枢神经系统。在发育方面，雏鸡脊髓运动神经元 具有良好的特征，尤其是在分化、成熟方面 和细胞死亡。因此，这个模型似乎是检验可能性的理想选择。 运动神经元功能障碍的生化和分子机制 死于发育障碍，如脊髓肌萎缩(SMA)。 在研究人员对运动神经元调节分子机制的研究中 在发育过程中死亡，他们发现其中一个信息是 在缺乏营养支持的运动神经元中上调的是APP。此外， APP是Caspase 3的底物，Caspase 3是一种被激活的蛋白酶 濒临死亡的运动神经元。此外，对这种分裂的抑制也阻止了 产生潜在毒性的β-淀粉样蛋白(Abeta)。这是第一次 这些分子之间直接相互作用的证据 随后得到了其他实验室的证实。此外，他们的数据还 提示APP参与神经元死亡是更多 APP和Abeta在调节细胞间相互作用中的生理作用 发育中的胆碱能运动神经元及其肌肉靶标。而当 最近的报告表明，这两种分子都与阿尔茨海默氏症有关 疾病，他们的结果表明，APP， 半胱氨酸天冬氨酸氨基转移酶和Aβ介导神经元在发育过程中的死亡 儿科神经病理学。该方案中的实验旨在 检测APP和Abeta的外观和功能 鸡脊髓运动神经元的发育系统。这些结果具有 有可能提供对分子的新见解 SMA背后的运动神经元死亡。

DESCRIPTION (adapted from applicant's abstract): Development of the central nervous system (CNS) includes events of histogenesis, differentiation, migration, cell interactions (including afferents, targets, surrounding cells) and cell death. Many individual factors play key roles in CNS development including extracellular matrix molecules, trophic factors, cytokines and individual cellular components. The interaction of factors and cells insures that the above developmental events lead to development of a functional, mature CNS. Studies of these events contribute not only to our understanding of developmental processes, but also lay the foundations for understanding pathological conditions, especially those that occur in disorders of the pediatric CNS. With regard to development, chick spinal motoneurons have been well characterized, especially with regard to their differentiation, maturation and cell death. As a result, this model appears ideal to examine possible biochemical and molecular mechanisms that underlie motoneuron dysfunction and death in developmental disorders such as the Spinal Muscular Atrophies (SMAs). In the investigators' studies of the molecular mechanisms mediating motoneuron death during development, they have discovered that one of the messages that is up-regulated in motoneurons deprived of trophic support is APP. Furthermore, APP serves as a substrate for Caspase 3, one of the proteases that is activated in dying motoneurons. Additionally, inhibition of this cleavage prevented production of potentially toxic beta-amyloid (Abeta). This was the first evidence for a direct interaction between these molecules that has been subsequently confirmed by other laboratories. Additionally, their data also suggest that APP's involvement in neuronal death is the consequence of a more physiological role for APP and Abeta in regulating interaction between cholinergic motoneurons with their muscle targets during development. While recent reports indicate that both molecules are involved in Alzheimer's Disease, their results suggest an intracellular mechanism by which APP, caspases and Abeta mediate neuronal death during development and possibly in pediatric neuropathologies. Experiments in this proposal are designed to examine the appearance and function of APP and Abeta in the well characterized developmental system of chick spinal motoneurons. These results have the potential to provide novel insights into the molecules that contribute to motoneuron death underlying the SMAs.