APP & MOTONEURON DEATH--PEDIATRIC CNS INJURY

描述（改编自申请人的摘要）： 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 单独的细胞成分。因子和细胞的相互作用 上述发育事件导致功能性、成熟的 CNS。对这些事件的研究不仅有助于我们理解 发展过程，但也奠定了理解的基础 病理状况，尤其是那些发生在疾病的 小儿中枢神经系统关于发育，小鸡脊髓运动神经元已经被 很好地描述，特别是关于它们的分化，成熟 和细胞死亡。因此，这个模型似乎是理想的检查可能的 运动神经元功能障碍的生化和分子机制， 发育障碍如脊髓性肌萎缩症（SMA）中的死亡。 在研究者们对运动神经元介导的分子机制的研究中， 在发展过程中死亡，他们发现， 在被剥夺营养支持的运动神经元中上调的是APP。此外， APP作为Caspase 3的底物，Caspase 3是被激活的蛋白酶之一， 在垂死的运动神经元中此外，抑制这种切割防止了 产生潜在毒性的β-淀粉样蛋白（Abeta）。这是第一 这些分子之间直接相互作用的证据 随后被其他实验室证实。此外，他们的数据还 这表明APP参与神经元死亡是一个更复杂的过程的结果。 APP和Abeta在调节 胆碱能运动神经元与其肌肉靶点在发育过程中。而 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， 半胱天冬酶和Abeta在发育过程中介导神经元死亡， 小儿神经病理学本提案中的实验旨在 检查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 潜在的提供新的见解的分子，有助于 运动神经元的死亡。

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.