Stem Cell Therapy and Growth Factor Therapy for ALS

肌萎缩侧索硬化症(ALS)导致运动神经元变性。脊髓腰部运动神经元的丢失会导致肢体瘫痪，而颈部呼吸运动神经元的丢失仍然是疾病进展的决定性时刻，导致呼吸机衰竭和呼吸机依赖。而当 尽管对肌萎缩侧索硬化症发病细胞机制的研究正在产生重要和新颖的见解，但这种方法尚未产生显著改善肌萎缩侧索硬化症患者健康的新药。由于运动神经元死亡的细胞机制可能极其复杂，很难用单一的 对于小分子，我们提出了一种更务实的方法。广泛的长期目标和目的是通过(I)利用内在的可塑性机制，(Ii)提供营养支持或(Iii)使用人类胚胎干细胞(HES)修复运动神经元来保护或恢复运动神经元。为了实现这些目标，有三个目标 高度互动的项目将评估运动神经元功能和在建立良好的ALS大鼠模型中的存活率。项目1将使用解剖学、生理学和行为学的方法来确定ALS大鼠呼吸的准确变化，以及该系统中运动神经元的死亡是否可以通过刺激内源性可塑性来调节。项目2将探索一个 干细胞来源的胶质细胞与GDNF、IGF-1、VEGF、BDNF等营养因子联合应用可减少ALS大鼠运动神经元的死亡，增强其功能。项目3将使用从HES细胞中提取运动神经元的尖端方法，并确定它们是否可以在ALS大鼠的脊髓中存活并与肌肉进行新的接触。关于增长因素各自作用的问题， 星形胶质细胞和运动神经元在运动神经元变性的病理中将在整个项目中不断得到解决。Pi‘s是呼吸神经生物学、人类胚胎干细胞、生长因子和HES细胞领域的知名研究人员。他们将协同工作，分享成果和想法，朝着这笔P01赠款的共同目标迈进。这项研究直接解决了 美国国立卫生研究院：即将获得关于对患者健康产生影响的特定不治之症的基本知识。此外，所采取的许多方法都与治疗策略直接相关，因为干细胞移植是这种毁灭性疾病未来真正的可能性。

Amyotrophic lateral sclerosis (ALS) causes degeneration of motor neurons. Motor neuron loss within lumbar regions of the spinal cord leads to limb paralysis while loss of cervical respiratory motor neurons remains a defining moment in disease progression, leading to ventilatory failure and ventilator dependence. While investigations of pathogenic cellular mechanisms that underlie ALS are yielding important and novel insights, this approach has not yet produced new drugs that significantly improve the health of ALS patients. Since the cellular mechanisms of motor neuron death may be extremely complex and difficult to block with a single small molecule, we propose a more pragmatic approach. The broad long term objectives and aims are to protect or restore motor neurons by either (i) harnessing intrinsic mechanisms of plasticity, (ii) providing trophic support or (iii) repacement using human embryonic stem (hES) cells. To achieve these aims, three highly interactive projects will assess motor neuron function and survival in a well established rat model of ALS. Project 1 will use anatomical, physiological and behavioral approaches to determine the precise changes in respiration that occur in the ALS rat, and whether the death of motor neurons within this system can be modulated through stimulation of endogenous plasticity. Project 2 will explore whether a combination of stem cell derived glial cells and trophic factors such as GDNF, IGF-1, VEGF and BDNF can reduce motor neuron cell death and enhance function in the ALS rat. Project 3 will use cutting edge methods of deriving motor neurons from hES cells and establish whether they can survive in the ALS rat spinal cord and make new contacts with muscle. Questions regarding the respective roles of growth factors, astrocytes and motor neurons in the pathology of motor neuron degeneration will be constantly addressed throughout this project. The Pi's are established researchers in their fields of respiratory neurobiology, human fetal stem cells, growth factors and hES cells. They will work synergistically, share results and ideas and move towards the common goals of this P01 grant. This study directly addresses the major goal of the NIH: i.e. essential knowledge will be gained about a specific incurable disease that will have an impact on the health of patients. Furthermore, many of the approaches taken have direct relevance to treatment strategies as transplantation of stem cells is a real future possibility for this devastating disorder.