Novel approaches to neural regeneration: Defining new genes & pathways

神经元损伤，如脊髓损伤，是毁灭性的，通常会导致生活质量的极度下降。在美国，仅脊髓损伤就影响约15，000人/年;这些患者中约有10，000人将永久瘫痪，许多其他人因受伤而死亡。很少有方法可以治疗这种毁灭性的损伤，这在很大程度上是因为由于过程的复杂性和可用于解决问题的有限系统，对影响再生的生物学途径和基因知之甚少。新的见解可能不仅适用于脊髓损伤，而且适用于脑外伤，中风和神经退行性疾病。我们建议开发一个首要的模式生物系统-果蝇-作为一个新的实验范式成人阶段的神经再生。在活体成年动物的初步研究中，我们用激光切断了翅膀神经束，观察到神经束的变性。惊人的初步观察表明，经过3周的静止期，神经束再生约40%的动物。我们将对这种神经损伤实验范式进行详细的表征，包括退化的程度和速度，以及再生的程度，速度和准确性。然后，使用这个系统，我们将利用果蝇中可用的分子定义的基因突变体来识别新的基因和途径。由于基线再生出现部分，这个实验范式将揭示影响退化的途径，以及那些调节再生。这些研究将为再生研究建立新的实验范式，揭示新的分子和途径，为神经损伤，损伤和退行性疾病的新疗法的发现提供基本的生物学见解和基础。

Project Summary - Neuronal injury, such as spinal cord damage, is devastating and typically leads to extreme reduction in life quality. Spinal cord injuries alone affect ~15,000 people/year in the US; about 10,000 of these patients will be permanently paralyzed and many others die due to their injuries. Few approaches are available to treat such devastating injuries, in large part because little is clear about biological pathways & genes that influence regeneration, due to the complexity of the process and the limited systems available for attacking the problem. New insight may be applicable not only to spinal cord injury, but also to brain trauma, stroke and neurodegenerative disease. We propose to develop one of the premier model organism systems-Drosophila-as a new experimental paradigm for adult-stage neural regeneration. In pilot studies in living adult animals, we have severed the wing nerve bundle with a laser and observed degeneration of the nerve tract. Striking preliminary observations show that after a 3-week quiescent period, the nerve bundle regenerates in about 40% of the animals. We will perform detailed characterization of this nerve injury experimental paradigm, including extent and speed of degeneration, as well as extent, speed and accuracy of regeneration. Then, using this system, we will exploit the available sets of molecularly-defined gene mutants in the fly to identify new genes & pathways. Because the baseline regeneration appears partial, this experimental paradigm will reveal both pathways that influence degeneration, as well as those that modulate regeneration. These studies will establish a new experimental paradigm for regeneration studies, and reveal new molecules & pathways, providing basic biological insight and the foundation for discovery of novel therapeutics for nerve injury, damage and degenerative disease.